Diseases characterized by the presence of abnormally phosphorylated, ubiquitinated, and cleaved DNA-binding protein TDP-43 in affected brain and spinal cord. Inclusions of the pathologic protein in neurons and glia, without the presence of AMYLOID, is the major feature of these conditions, thus making these proteinopathies distinct from most other neurogenerative disorders in which protein misfolding leads to brain amyloidosis. Both frontotemporal lobar degeneration and AMYOTROPHIC LATERAL SCLEROSIS exhibit this common method of pathogenesis and thus they may represent two extremes of a continuous clinicopathological spectrum of one disease.
A generic term for any circumscribed mass of foreign (e.g., lead or viruses) or metabolically inactive materials (e.g., ceroid or MALLORY BODIES), within the cytoplasm or nucleus of a cell. Inclusion bodies are in cells infected with certain filtrable viruses, observed especially in nerve, epithelial, or endothelial cells. (Stedman, 25th ed)
Heterogeneous group of neurodegenerative disorders characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Multiple subtypes or forms are recognized based on presence or absence of TAU PROTEIN inclusions. FTLD includes three clinical syndromes: FRONTOTEMPORAL DEMENTIA, semantic dementia, and PRIMARY PROGRESSIVE NONFLUENT APHASIA.
A degenerative disorder affecting upper MOTOR NEURONS in the brain and lower motor neurons in the brain stem and SPINAL CORD. Disease onset is usually after the age of 50 and the process is usually fatal within 3 to 6 years. Clinical manifestations include progressive weakness, atrophy, FASCICULATION, hyperreflexia, DYSARTHRIA, dysphagia, and eventual paralysis of respiratory function. Pathologic features include the replacement of motor neurons with fibrous ASTROCYTES and atrophy of anterior SPINAL NERVE ROOTS and corticospinal tracts. (From Adams et al., Principles of Neurology, 6th ed, pp1089-94)
The most common clinical form of FRONTOTEMPORAL LOBAR DEGENERATION, this dementia presents with personality and behavioral changes often associated with disinhibition, apathy, and lack of insight.
Diseases characterized by a selective degeneration of the motor neurons of the spinal cord, brainstem, or motor cortex. Clinical subtypes are distinguished by the major site of degeneration. In AMYOTROPHIC LATERAL SCLEROSIS there is involvement of upper, lower, and brainstem motor neurons. In progressive muscular atrophy and related syndromes (see MUSCULAR ATROPHY, SPINAL) the motor neurons in the spinal cord are primarily affected. With progressive bulbar palsy (BULBAR PALSY, PROGRESSIVE), the initial degeneration occurs in the brainstem. In primary lateral sclerosis, the cortical neurons are affected in isolation. (Adams et al., Principles of Neurology, 6th ed, p1089)
A multifunctional heterogeneous-nuclear ribonucleoprotein that may play a role in homologous DNA pairing and recombination. The N-terminal portion of protein is a potent transcriptional activator, while the C terminus is required for RNA binding. The name FUS refers to the fact that genetic recombination events result in fusion oncogene proteins (ONCOGENE PROTEINS, FUSION) that contain the N-terminal region of this protein. These fusion proteins have been found in myxoid liposarcoma (LIPOSARCOMA, MYXOID) and acute myeloid leukemia.
Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures.
Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.
An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness.
The segregation and degradation of damaged or unwanted cytoplasmic constituents by autophagic vacuoles (cytolysosomes) composed of LYSOSOMES containing cellular components in the process of digestion; it plays an important role in BIOLOGICAL METAMORPHOSIS of amphibians, in the removal of bone by osteoclasts, and in the degradation of normal cell components in nutritional deficiency states.
The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.
A malignant form of polymorphic ventricular tachycardia that is characterized by HEART RATE between 200 and 250 beats per minute, and QRS complexes with changing amplitude and twisting of the points. The term also describes the syndrome of tachycardia with prolonged ventricular repolarization, long QT intervals exceeding 500 milliseconds or BRADYCARDIA. Torsades de pointes may be self-limited or may progress to VENTRICULAR FIBRILLATION.
A class of enzymes that catalyze the hydrolysis of one of the two ester bonds in a phosphodiester compound. EC 3.1.4.
Extensions of the nerve cell body. They are short and branched and receive stimuli from other NEURONS.
An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1.
Neurons which activate MUSCLE CELLS.
Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.
The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.
Spiny processes on DENDRITES, each of which receives excitatory input from one nerve ending (NERVE ENDINGS). They are commonly found on PURKINJE CELLS and PYRAMIDAL CELLS.

Sporadic corticobasal syndrome due to FTLD-TDP. (1/53)

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Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6. (2/53)

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Neuropathology of non-Alzheimer degenerative disorders. (3/53)

Neurodegenerative diseases are characterized by selective and progressive loss of specific populations of neurons, which determines the clinical presentation. The same neuronal populations can be affected in a number of different disorders. Given that the clinical presentation reflects the particular population of neurons that are targets of the disease process, it is clear that for any given clinical syndrome, more than one neurodegenerative disease can account for the clinical syndrome. Because of this clinical ambiguity, for the purpose of this brief review neurodegenerative disorders are classified according to the underlying molecular pathology rather than their clinical presentation. The major neurodegenerative diseases can be classified into amyloidoses, tauopathies, alpha-synucleinopathies and TDP-43 proteinopathies.  (+info)

Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis. (4/53)

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Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains. (5/53)

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A Drosophila model for TDP-43 proteinopathy. (6/53)

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Review: transactive response DNA-binding protein 43 (TDP-43): mechanisms of neurodegeneration. (7/53)

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TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease. (8/53)

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TDP-43 proteinopathies refer to a group of neurodegenerative disorders characterized by the abnormal accumulation and aggregation of the TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells. The accumulated TDP-43 forms inclusions that are rich in ubiquitin and are a hallmark of these disorders.

TDP-43 is a nuclear protein involved in various cellular processes, including transcription, splicing, and transport of RNA. In TDP-43 proteinopathies, the protein undergoes post-translational modifications that lead to its mislocalization from the nucleus to the cytoplasm, where it forms aggregates.

TDP-43 proteinopathies include several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD). In ALS, TDP-43 pathology is present in almost all cases, while in FTLD, it is found in about half of the cases. In AD, TDP-43 pathology is less common but still significant, particularly in patients with coexisting dementia.

TDP-43 proteinopathies are associated with various clinical manifestations depending on the specific disorder and the extent and location of TDP-43 aggregation. These manifestations include motor neuron degeneration, cognitive decline, behavioral changes, and language impairments. The underlying mechanisms leading to TDP-43 mislocalization and aggregation are not fully understood but are thought to involve genetic, environmental, and aging factors.

Inclusion bodies are abnormal, intracellular accumulations or aggregations of various misfolded proteins, protein complexes, or other materials within the cells of an organism. They can be found in various tissues and cell types and are often associated with several pathological conditions, including infectious diseases, neurodegenerative disorders, and genetic diseases.

Inclusion bodies can vary in size, shape, and location depending on the specific disease or condition. Some inclusion bodies have a characteristic appearance under the microscope, such as eosinophilic (pink) staining with hematoxylin and eosin (H&E) histological stain, while others may require specialized stains or immunohistochemical techniques to identify the specific misfolded proteins involved.

Examples of diseases associated with inclusion bodies include:

1. Infectious diseases: Some viral infections, such as HIV, hepatitis B and C, and herpes simplex virus, can lead to the formation of inclusion bodies within infected cells.
2. Neurodegenerative disorders: Several neurodegenerative diseases are characterized by the presence of inclusion bodies, including Alzheimer's disease (amyloid-beta plaques and tau tangles), Parkinson's disease (Lewy bodies), Huntington's disease (Huntingtin aggregates), and amyotrophic lateral sclerosis (TDP-43 and SOD1 inclusions).
3. Genetic diseases: Certain genetic disorders, such as Danon disease, neuronal intranuclear inclusion disease, and some lysosomal storage disorders, can also present with inclusion bodies due to the accumulation of abnormal proteins or metabolic products within cells.

The exact role of inclusion bodies in disease pathogenesis remains unclear; however, they are often associated with cellular dysfunction, oxidative stress, and increased inflammation, which can contribute to disease progression and neurodegeneration.

Frontotemporal lobar degeneration (FTLD) is a group of disorders characterized by the progressive degeneration of the frontal and temporal lobes of the brain. These areas of the brain are involved in decision-making, behavior, emotion, and language. FTLD can be divided into several subtypes based on the specific clinical features and the underlying protein abnormalities.

The three main subtypes of FTLD are:

1. Behavioral variant frontotemporal dementia (bvFTD): This subtype is characterized by changes in personality, behavior, and judgment. People with bvFTD may lose their social inhibitions, become impulsive, or develop compulsive behaviors. They may also have difficulty with emotional processing and empathy.
2. Primary progressive aphasia (PPA): This subtype is characterized by the gradual deterioration of language skills. People with PPA may have difficulty speaking, understanding spoken or written language, or both. There are three subtypes of PPA: nonfluent/agrammatic variant, semantic variant, and logopenic variant.
3. Motor neuron disease (MND) with FTLD: This subtype is characterized by the degeneration of motor neurons, which are the nerve cells responsible for controlling voluntary muscle movements. People with MND with FTLD may develop symptoms of amyotrophic lateral sclerosis (ALS), such as muscle weakness, stiffness, and twitching, as well as cognitive and behavioral changes associated with FTLD.

The underlying protein abnormalities in FTLD include:

1. Tau protein: In some forms of FTLD, the tau protein accumulates and forms clumps called tangles inside nerve cells. This is also seen in Alzheimer's disease.
2. TDP-43 protein: In other forms of FTLD, the TDP-43 protein accumulates and forms clumps inside nerve cells.
3. Fused in sarcoma (FUS) protein: In a small number of cases, the FUS protein accumulates and forms clumps inside nerve cells.

FTLD is typically a progressive disorder, meaning that symptoms worsen over time. There is currently no cure for FTLD, but there are treatments available to help manage symptoms and improve quality of life.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder that affects nerve cells in the brain and spinal cord responsible for controlling voluntary muscle movements, such as speaking, walking, breathing, and swallowing. The condition is characterized by the degeneration of motor neurons in the brain (upper motor neurons) and spinal cord (lower motor neurons), leading to their death.

The term "amyotrophic" comes from the Greek words "a" meaning no or negative, "myo" referring to muscle, and "trophic" relating to nutrition. When a motor neuron degenerates and can no longer send impulses to the muscle, the muscle becomes weak and eventually atrophies due to lack of use.

The term "lateral sclerosis" refers to the hardening or scarring (sclerosis) of the lateral columns of the spinal cord, which are primarily composed of nerve fibers that carry information from the brain to the muscles.

ALS is often called Lou Gehrig's disease, named after the famous American baseball player who was diagnosed with the condition in 1939. The exact cause of ALS remains unknown, but it is believed to involve a combination of genetic and environmental factors. There is currently no cure for ALS, and treatment primarily focuses on managing symptoms and maintaining quality of life.

The progression of ALS varies from person to person, with some individuals experiencing rapid decline over just a few years, while others may have a more slow-progressing form of the disease that lasts several decades. The majority of people with ALS die from respiratory failure within 3 to 5 years after the onset of symptoms. However, approximately 10% of those affected live for 10 or more years following diagnosis.

Frontotemporal dementia (FTD) is a group of disorders caused by progressive degeneration of the frontal and temporal lobes of the brain. These areas of the brain are associated with personality, behavior, and language.

There are three main types of FTD:

1. Behavioral variant FTD (bvFTD): This type is characterized by changes in personality, behavior, and judgment. Individuals may become socially inappropriate, emotionally indifferent, or impulsive. They may lose interest in things they used to enjoy and have difficulty with tasks that require planning and organization.

2. Primary progressive aphasia (PPA): This type affects language abilities. There are two main subtypes of PPA: semantic dementia and progressive nonfluent aphasia. Semantic dementia is characterized by difficulty understanding words and objects, while progressive nonfluent aphasia is characterized by problems with speech production and articulation.

3. Motor neuron disease (MND) associated FTD: Some individuals with FTD may also develop motor neuron disease, which affects the nerves that control muscle movement. This can lead to weakness, stiffness, and wasting of muscles, as well as difficulty swallowing and speaking.

FTD is a degenerative disorder, meaning that symptoms get worse over time. There is no cure for FTD, but there are treatments available to help manage symptoms and improve quality of life. The exact cause of FTD is not known, but it is believed to be related to abnormalities in certain proteins in the brain. In some cases, FTD may run in families and be caused by genetic mutations.

Motor Neuron Disease (MND) is a progressive neurodegenerative disorder that affects the motor neurons, which are nerve cells in the brain and spinal cord responsible for controlling voluntary muscles involved in movement, speaking, breathing, and swallowing. As the motor neurons degenerate and die, they stop sending signals to the muscles, causing them to weaken, waste away (atrophy), and eventually lead to paralysis.

There are several types of MND, including:

1. Amyotrophic Lateral Sclerosis (ALS): Also known as Lou Gehrig's disease, this is the most common form of MND. It affects both upper and lower motor neurons, causing muscle weakness, stiffness, twitching, and atrophy throughout the body.
2. Progressive Bulbar Palsy (PBP): This type primarily affects the bulbar muscles in the brainstem, which control speech, swallowing, and chewing. Patients with PBP experience difficulties with speaking, slurred speech, and problems swallowing and may also have weak facial muscles and limb weakness.
3. Primary Lateral Sclerosis (PLS): This form of MND affects only the upper motor neurons, causing muscle stiffness, spasticity, and weakness, primarily in the legs. PLS progresses more slowly than ALS, and patients usually maintain their ability to speak and swallow for a longer period.
4. Progressive Muscular Atrophy (PMA): This type of MND affects only the lower motor neurons, causing muscle wasting, weakness, and fasciculations (muscle twitches). PMA progresses more slowly than ALS but can still be severely disabling over time.
5. Spinal Muscular Atrophy (SMA): This is a genetic form of MND that typically presents in infancy or childhood, although adult-onset forms exist. SMA affects the lower motor neurons in the spinal cord, causing muscle weakness and atrophy, primarily in the legs and trunk.

The exact cause of Motor Neuron Disease is not fully understood, but it is believed to involve a combination of genetic, environmental, and lifestyle factors. There is currently no cure for MND, and treatment focuses on managing symptoms, maintaining quality of life, and slowing disease progression through various therapies and medications.

FUS (Fused in Sarcoma) is a protein that in humans is encoded by the FUS gene. It is primarily located in the nucleus of the cell, but can also be found in the cytoplasm. FUS belongs to the family of RNA-binding proteins, which means it has the ability to bind to RNA molecules and play a role in post-transcriptional regulation of gene expression.

FUS has several functions, including:

1. Transcriptional regulation: FUS can interact with transcription factors and modulate the transcription of genes.
2. mRNA processing: FUS is involved in various aspects of mRNA processing, such as splicing, transport, localization, and stability.
3. DNA repair: FUS plays a role in DNA damage response and repair mechanisms.
4. Translational regulation: FUS can also regulate translation by interacting with ribosomes and other translational factors.

Mutations in the FUS gene have been associated with several neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). These mutations often lead to an abnormal cytoplasmic accumulation of FUS protein, which can form aggregates and contribute to the pathogenesis of these diseases.

Neurodegenerative diseases are a group of disorders characterized by progressive and persistent loss of neuronal structure and function, often leading to cognitive decline, functional impairment, and ultimately death. These conditions are associated with the accumulation of abnormal protein aggregates, mitochondrial dysfunction, oxidative stress, chronic inflammation, and genetic mutations in the brain. Examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis (ALS), and Spinal Muscular Atrophy (SMA). The underlying causes and mechanisms of these diseases are not fully understood, and there is currently no cure for most neurodegenerative disorders. Treatment typically focuses on managing symptoms and slowing disease progression.

DNA-binding proteins are a type of protein that have the ability to bind to DNA (deoxyribonucleic acid), the genetic material of organisms. These proteins play crucial roles in various biological processes, such as regulation of gene expression, DNA replication, repair and recombination.

The binding of DNA-binding proteins to specific DNA sequences is mediated by non-covalent interactions, including electrostatic, hydrogen bonding, and van der Waals forces. The specificity of binding is determined by the recognition of particular nucleotide sequences or structural features of the DNA molecule.

DNA-binding proteins can be classified into several categories based on their structure and function, such as transcription factors, histones, and restriction enzymes. Transcription factors are a major class of DNA-binding proteins that regulate gene expression by binding to specific DNA sequences in the promoter region of genes and recruiting other proteins to modulate transcription. Histones are DNA-binding proteins that package DNA into nucleosomes, the basic unit of chromatin structure. Restriction enzymes are DNA-binding proteins that recognize and cleave specific DNA sequences, and are widely used in molecular biology research and biotechnology applications.

Dementia is a broad term that describes a decline in cognitive functioning, including memory, language, problem-solving, and judgment, severe enough to interfere with daily life. It is not a specific disease but rather a group of symptoms that may be caused by various underlying diseases or conditions. Alzheimer's disease is the most common cause of dementia, accounting for 60-80% of cases. Other causes include vascular dementia, Lewy body dementia, frontotemporal dementia, and Huntington's disease.

The symptoms of dementia can vary widely depending on the cause and the specific areas of the brain that are affected. However, common early signs of dementia may include:

* Memory loss that affects daily life
* Difficulty with familiar tasks
* Problems with language or communication
* Difficulty with visual and spatial abilities
* Misplacing things and unable to retrace steps
* Decreased or poor judgment
* Withdrawal from work or social activities
* Changes in mood or behavior

Dementia is a progressive condition, meaning that symptoms will gradually worsen over time. While there is currently no cure for dementia, early diagnosis and treatment can help slow the progression of the disease and improve quality of life for those affected.

Autophagy is a fundamental cellular process that involves the degradation and recycling of damaged or unnecessary cellular components, such as proteins and organelles. The term "autophagy" comes from the Greek words "auto" meaning self and "phagy" meaning eating. It is a natural process that occurs in all types of cells and helps maintain cellular homeostasis by breaking down and recycling these components.

There are several different types of autophagy, including macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy is the most well-known form and involves the formation of a double-membraned vesicle called an autophagosome, which engulfs the cellular component to be degraded. The autophagosome then fuses with a lysosome, an organelle containing enzymes that break down and recycle the contents of the autophagosome.

Autophagy plays important roles in various cellular processes, including adaptation to starvation, removal of damaged organelles, clearance of protein aggregates, and regulation of programmed cell death (apoptosis). Dysregulation of autophagy has been implicated in a number of diseases, including cancer, neurodegenerative disorders, and infectious diseases.

The brain is the central organ of the nervous system, responsible for receiving and processing sensory information, regulating vital functions, and controlling behavior, movement, and cognition. It is divided into several distinct regions, each with specific functions:

1. Cerebrum: The largest part of the brain, responsible for higher cognitive functions such as thinking, learning, memory, language, and perception. It is divided into two hemispheres, each controlling the opposite side of the body.
2. Cerebellum: Located at the back of the brain, it is responsible for coordinating muscle movements, maintaining balance, and fine-tuning motor skills.
3. Brainstem: Connects the cerebrum and cerebellum to the spinal cord, controlling vital functions such as breathing, heart rate, and blood pressure. It also serves as a relay center for sensory information and motor commands between the brain and the rest of the body.
4. Diencephalon: A region that includes the thalamus (a major sensory relay station) and hypothalamus (regulates hormones, temperature, hunger, thirst, and sleep).
5. Limbic system: A group of structures involved in emotional processing, memory formation, and motivation, including the hippocampus, amygdala, and cingulate gyrus.

The brain is composed of billions of interconnected neurons that communicate through electrical and chemical signals. It is protected by the skull and surrounded by three layers of membranes called meninges, as well as cerebrospinal fluid that provides cushioning and nutrients.

Torsades de Pointes is a type of polymorphic ventricular tachycardia, characterized by a distinct pattern on the electrocardiogram (ECG) where the QRS complexes appear to twist around the isoelectric line. This condition is often associated with a prolonged QT interval, which can be congenital or acquired due to various factors such as medications, electrolyte imbalances, or heart diseases. Torsades de Pointes can degenerate into ventricular fibrillation, leading to sudden cardiac death if not promptly treated.

Phosphoric diester hydrolases are a class of enzymes that catalyze the hydrolysis of phosphoric diester bonds. These enzymes are also known as phosphatases or nucleotidases. They play important roles in various biological processes, such as signal transduction, metabolism, and regulation of cellular activities.

Phosphoric diester hydrolases can be further classified into several subclasses based on their substrate specificity and catalytic mechanism. For example, alkaline phosphatases (ALPs) are a group of phosphoric diester hydrolases that preferentially hydrolyze phosphomonoester bonds in a variety of organic molecules, releasing phosphate ions and alcohols. On the other hand, nucleotidases are a subclass of phosphoric diester hydrolases that specifically hydrolyze the phosphodiester bonds in nucleotides, releasing nucleosides and phosphate ions.

Overall, phosphoric diester hydrolases are essential for maintaining the balance of various cellular processes by regulating the levels of phosphorylated molecules and nucleotides.

Dendrites are the branched projections of a neuron that receive and process signals from other neurons. They are typically short and highly branching, increasing the surface area for receiving incoming signals. Dendrites are covered in small protrusions called dendritic spines, which can form connections with the axon terminals of other neurons through chemical synapses. The structure and function of dendrites play a critical role in the integration and processing of information in the nervous system.

Medical Definition:

Superoxide dismutase (SOD) is an enzyme that catalyzes the dismutation of superoxide radicals (O2-) into oxygen (O2) and hydrogen peroxide (H2O2). This essential antioxidant defense mechanism helps protect the body's cells from damage caused by reactive oxygen species (ROS), which are produced during normal metabolic processes and can lead to oxidative stress when their levels become too high.

There are three main types of superoxide dismutase found in different cellular locations:
1. Copper-zinc superoxide dismutase (CuZnSOD or SOD1) - Present mainly in the cytoplasm of cells.
2. Manganese superoxide dismutase (MnSOD or SOD2) - Located within the mitochondrial matrix.
3. Extracellular superoxide dismutase (EcSOD or SOD3) - Found in the extracellular spaces, such as blood vessels and connective tissues.

Imbalances in SOD levels or activity have been linked to various pathological conditions, including neurodegenerative diseases, cancer, and aging-related disorders.

Motor neurons are specialized nerve cells in the brain and spinal cord that play a crucial role in controlling voluntary muscle movements. They transmit electrical signals from the brain to the muscles, enabling us to perform actions such as walking, talking, and swallowing. There are two types of motor neurons: upper motor neurons, which originate in the brain's motor cortex and travel down to the brainstem and spinal cord; and lower motor neurons, which extend from the brainstem and spinal cord to the muscles. Damage or degeneration of these motor neurons can lead to various neurological disorders, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).

Transgenic mice are genetically modified rodents that have incorporated foreign DNA (exogenous DNA) into their own genome. This is typically done through the use of recombinant DNA technology, where a specific gene or genetic sequence of interest is isolated and then introduced into the mouse embryo. The resulting transgenic mice can then express the protein encoded by the foreign gene, allowing researchers to study its function in a living organism.

The process of creating transgenic mice usually involves microinjecting the exogenous DNA into the pronucleus of a fertilized egg, which is then implanted into a surrogate mother. The offspring that result from this procedure are screened for the presence of the foreign DNA, and those that carry the desired genetic modification are used to establish a transgenic mouse line.

Transgenic mice have been widely used in biomedical research to model human diseases, study gene function, and test new therapies. They provide a valuable tool for understanding complex biological processes and developing new treatments for a variety of medical conditions.

Neurons, also known as nerve cells or neurocytes, are specialized cells that constitute the basic unit of the nervous system. They are responsible for receiving, processing, and transmitting information and signals within the body. Neurons have three main parts: the dendrites, the cell body (soma), and the axon. The dendrites receive signals from other neurons or sensory receptors, while the axon transmits these signals to other neurons, muscles, or glands. The junction between two neurons is called a synapse, where neurotransmitters are released to transmit the signal across the gap (synaptic cleft) to the next neuron. Neurons vary in size, shape, and structure depending on their function and location within the nervous system.

Dendritic spines are small, specialized protrusions found on the dendrites of neurons, which are cells that transmit information in the nervous system. These structures receive and process signals from other neurons. Dendritic spines have a small head connected to the dendrite by a thin neck, and they vary in shape, size, and number depending on the type of neuron and its function. They are dynamic structures that can change their morphology and strength of connections with other neurons in response to various stimuli, such as learning and memory processes.

... or proteinopathy) deposits in the brain that characterize LATE, and "encephalopathy" means illness of brain. At present LATE ... The acronym LATE stands for Limbic-predominant Age-related TDP-43 Encephalopathy: "limbic" is related to the brain areas first ... Chornenkyy, Yevgen; Fardo, David W.; Nelson, Peter T. (July 2019). "Tau and TDP-43 proteinopathies: kindred pathologic cascades ... Chen, Han-Jou; Mitchell, Jacqueline C. (2021-06-02). "Mechanisms of TDP-43 Proteinopathy Onset and Propagation". International ...
McKee, AC, Gavett, Brandon E, Stern, Robert A, Nowinski, Christopher, Cantu, Robert C (September 2010). "TDP-43 Proteinopathy ... She died 43 years after Gehrig on her 80th birthday, March 6, 1984, and was interred with him in Kensico Cemetery. Despite ...
TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. Journal of Neuropathology & Experimental ...
Ito D, Suzuki N (October 2011). "Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS ... In medicine, proteinopathy ([pref. protein]; -pathy [suff. disease]; proteinopathies pl.; proteinopathic adj), or proteopathy, ... The likelihood that proteinopathy will develop is increased by certain risk factors that promote the self-assembly of a protein ... The proteinopathies include such diseases as Creutzfeldt-Jakob disease and other prion diseases, Alzheimer's disease, ...
FTLD-TDP (or FTLD-U ) is characterised by ubiquitin and TDP-43 positive, tau negative, FUS negative inclusion bodies. The ... Common proteinopathies that are found in FTLD include the accumulation of tau proteins and TAR DNA-binding protein 43 (TDP-43 ... FTLD-TDP43). Patients with progranulin mutations have type 3 ubiquitin-positive, TDP-43 positive, tau-negative pathology at ... "Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B not TDP-43". Nature. 605 (7909): 304-309. doi:10.1038/s41586-022- ...
... proteinopathy; hippocampal sclerosis often accompanied the FUS proteinopathy. In 1994, Dickson et al. described hippocampal ... 2015). "Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A". Acta Neuropathologica ... 2006). "Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis". Science. 314 (5796): 130- ... Hippocampal sclerosis occurs in about 60% of those with progressive supranuclear palsy TDP-43 proteinopathy (PSP-TDP) and in ...
March 2011). "TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor". ... March 2018). "TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations". The Journal of Clinical ... November 2009). "TDP-43 is recruited to stress granules in conditions of oxidative insult". Journal of Neurochemistry. 111 (4 ... Khalfallah Y, Kuta R, Grasmuck C, Prat A, Durham HD, Vande Velde C (May 2018). "TDP-43 regulation of stress granule dynamics in ...
... such as TDP-43, HNRNPA1, HNRNPA2B1, and other components of RNA granules. MSP is a dominantly inherited and genetically ... Multisystem proteinopathy (MSP) is a dominantly inherited, pleiotropic, degenerative disorder of humans that can affect muscle ...
It is thereby of the utmost importance to note that TDP-43's nuclear localization is absolutely critical for it to fulfill its ... March 2013). "Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS". Nature. 495 ( ... There are six mitochondrial localization signals to be accounted on TDP-43's amino acid sequence, although only M1, M3, and M5 ... The nuclear export signal is located between residues 239 and 251 sequence probably bears a role in TDP-43's shuttling function ...
FTD caused by FTLD-TDP43 has numerous genetic causes. Some cases are due to mutations in the GRN gene, also located on ... although these patients present with a complex picture of multisystem proteinopathy that can include amyotrophic lateral ... Only one or two cases have been reported describing TARDBP (the TDP-43 gene) mutations in a clinically-pure FTD (FTD without ... There are three main histological subtypes found at post-mortem: FTLD-tau, FTLD-TDP, and FTLD-FUS. In rare cases, patients with ...
Following up on earlier leads, the Greenberg group report finding that the protein TDP-43 is a very prominent and highly ... Mutations in valosin-containing protein (VCP) cause multisystem proteinopathy (MSP), which can present (among others) as a rare ... 2009). "Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis". Muscle Nerve. 40 (1): 19-31. doi:10.1002/mus ... "215th ENMC International Workshop VCP-related multi-system proteinopathy (IBMPFD) 13-15 November 2015, Heemskerk, The ...
Specifically, aggregation of TDP-43, an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes ... Golde TE, Borchelt DR, Giasson BI, Lewis J (May 2013). "Thinking laterally about neurodegenerative proteinopathies". The ... The misfolding of TDP-43 is largely directed by its prion-like domain. This domain is inherently prone to misfolding, while ... In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of Alzheimer's disease, Parkinson's disease and ...
TDP-43 is involved in the repair of DNA double-strand breaks. It is recruited to DNA damage sites and interacts with proteins ... "Mutations in the prion-like domains of hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS". Nature. 495 (7442): 467- ... The TDP-43 protein, coded for by the TARDBP gene, is responsible for regulation of RNA expression. The discovery of mutations ... SOD1 and TDP-43 mutations may play a role in causing mitochondria dysfunction. Increased markers of oxidative stress have been ...
More recently, TDP-43 and FUS protein aggregates have been implicated in some cases of the disease, and a mutation in ... like proteinopathy) and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative ... Plaques are made up of small peptides, typically 39-43 amino acids in length, called amyloid beta (also written as A-beta or Aβ ...
Investigating Distinct and Overlapping Mechanisms in TDP-43 Proteinopathies, including in LATE, FTD and other ADRDs (R01 - ... Many studies report the presence of pathologic TDP-43 (TAR DNA-binding protein 43, encoded by the TARDBP gene) in the brains of ... Mechanistic studies under this NOFO should focus on TDP-43, either alone or with other pathologies (e.g., TMEM106B, tau, alpha- ... Comparisons between TDP-43 proteinopathies are needed to determine commonalities and differences in cellular and molecular ...
TDP-43) inclusions frequently occur as a comorbid pathology in several neurodegenerative disorders, including Alzheimers ... Incidence and morphology of secondary TDP-43 proteinopathies: Part 2 Albert Acewicz 1 , Tomasz Stępień 1 , Paulina Felczak 1 , ... Incidence and morphology of secondary TDP-43 proteinopathies: Part 2 Albert Acewicz et al. Folia Neuropathol. 2023. ... The present review aims to discuss the incidence, morphology, and role of TDP-43 pathology in the context of other dominant, ...
Moreover, it has been reported that both a neuronal and a glial cell tauopathy can accompany the TDP-43 proteinopathy in ... Conversely, in FTD and FTD + MND dementia is more likely to be associated with TDP-43 proteinopathy than tau. Hence, present ... within the cerebral cortex rather than as a result of TDP-43 proteinopathy. ... Twenty four (59 %) patients with MND, 7 (44 %) patients with FTD + MND and 10 (43 %) patients with FTD showed ...
... or proteinopathy) deposits in the brain that characterize LATE, and "encephalopathy" means illness of brain. At present LATE ... The acronym LATE stands for Limbic-predominant Age-related TDP-43 Encephalopathy: "limbic" is related to the brain areas first ... Chornenkyy, Yevgen; Fardo, David W.; Nelson, Peter T. (July 2019). "Tau and TDP-43 proteinopathies: kindred pathologic cascades ... Chen, Han-Jou; Mitchell, Jacqueline C. (2021-06-02). "Mechanisms of TDP-43 Proteinopathy Onset and Propagation". International ...
TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6. * ... TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6. ... A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be ... These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 ...
... proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity ... proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity ... proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity ... proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity ...
TDP-43 has been identified as the major pathologic protein in sporadic ALS and has also been found in the most common ... Motor neuron involvement in multisystem proteinopathy: implications for ALS. Neurology. 2013 May 14. 80(20):1874-80. [QxMD ... Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations. Proc Natl Acad ... TDP-43 Redistribution Is an Early Event in Sporadic Amyotrophic Lateral Sclerosis. Brain Pathol. 2009 Mar 17. [QxMD MEDLINE ...
TDP-43 staging scheme in Alzheimers disease.. TOP RIGHT: Seddighi et al. (Preprint; 2023) Figure 2A.. Illustration of how RNA ... In a new preprint, Seddighi and colleagues show that TDP-43 depletion in iPSC-derived neurons leads to de novo "cryptic" ... Finally, Baughn and colleagues provide mechanistic insight into the function of TDP-43 and identify two methods to restore ... Microscope imaging showing in vitro axonal regeneration in neurons with TDP-43 pathology before rescue of the gene encoding ...
Hippocampal LFPI-induced TDP-43 pathology was not accompanied by the microglial reaction, contrary to the findings after rmTBI ... In the ipsilateral cortices of animals following LFPI, we found changes in the cytoplasmic and nuclear levels of TDP-43 and the ... Subacute pathological changes of TDP-43 in the hippocampi of animals following LFPI and in mice exposed to repetitive mild TBI ... We explored the acute cortical post-traumatic changes of TDP-43 using the lateral fluid percussion injury (LFPI) model of ...
Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Nature. 2020 12; 588(7838):459-465. View on PubMed ... Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology. Stem Cell Reports. 2023 03 ... TMIC-43. HEDGEHOG LIGANDS FROM GLIOBLASTOMA CELLS INDUCE ASTROCYTES INHIBITION OF CANCER STEM CELLS. Neuro-Oncology. 2022 Nov ...
miR-23a suppression accelerates functional decline in the rNLS8 mouse model of TDP-43 proteinopathy. Tsitkanou S, Della Gatta ...
Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Zhang J, Velmeshev D, Hashimoto K, Huang YH, ... 2021 Oct 20;43(3):1685-1697. doi: 10.3390/cimb43030119. Curr Issues Mol Biol. 2021. PMID: 34698115 Free PMC article. ...
7. PTK2/FAK regulates UPS impairment via SQSTM1/p62 phosphorylation in TARDBP/TDP-43 proteinopathies.. Lee S; Jeon YM; Cha SJ; ... Mol Cell Neurosci; 2018 Apr; 88():43-52. PubMed ID: 29246658. [TBL] ...
TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. Nature. PMID 35197626 DOI: 10.1038/s41586-022-04424-7 0.784 ... ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease. Neurocase. 19: 295-301. PMID 22512241 ... Detection of TDP-43 oligomers in frontotemporal lobar degeneration-TDP. Annals of Neurology. 78: 211-21. PMID 25921485 DOI: ... Mixed TDP-43 proteinopathy and tauopathy in frontotemporal lobar degeneration: nine case series. Journal of Neurology. PMID ...
Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimers disease, and ... Furthermore, Nlk reduction ameliorated pathological, behavioral, and life span deficits in 2 distinct mouse models of TDP-43 ... proteinopathy. Because many toxic proteins can be cleared through the autophagy/lysosome pathway, targeted reduction of Nlk ... Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. ...
Table 1 List of components of the UPS and autophagy related to proteinopathies. Full size table. ... A handful of genes harbor the majority of familial ALS mutations, including SOD1, TDP-43, FUS and C9orf72 (Bartoletti et al. ... Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a ... 2010). Importantly, TDP-43 and FUS-immunoreactive aggregates are also a common feature in sporadic ALS (Giordana et al. 2010; ...
History of clinically significant medical conditions (other than ALS) or any other reason, including any physical, psychological, or psychiatric condition that, in the opinion of the Investigator, would compromise the safety or interfere with the subjects participation in the study, or would make the subject an unsuitable candidate to receive study drug, or would put the subject at risk by participating in the study ...
TDP-43 in AD/ADRD: Establish biomarkers and dementia risk profiles Share: Print page Facebook share Linkedin share twitter ... TDP-43 in AD/ADRD: Establish biomarkers and dementia risk profiles (Milestone 9.T) In Progress ... At least three new projects to develop biomarker profiles for clinical trials for TDP-43 proteinopathy in common dementias. ... Currently, biomarkers that reveal pathological changes in TDP-43, a protein linked to various types of dementia, are needed ...
2(2) Determine the mechanism of TDP-43 and FUS pathogenesis and toxicity.. *Support research to identify the predominant ... 3(3) Examine the pathologic phenotype(s) of TDP-43 pathology in asymptomatic persons and those with common dementias.. * ... Develop, test, and pathologically confirm novel blood/CSF biomarkers or PET ligands for FTLD-tau, -TDP or -FUS during life, ... Develop, validate and make available to the broader scientific community two or more novel animal models that exhibit TDP-43 ...
It is expected that this effort might lead to the development of early markers of potential risk of developing proteinopathies ... TDP-43 (Frontotemporal dementia) and many more. In addition to neurodegeneration, disease-causing proteinopathies exist in the ... To explore this possibility, researchers working on varied proteinopathies will be convened, to discuss commonalities and ... Similarly, aggregates with different specific molecular identities are hallmarks for several other proteinopathies, and in fact ...
Armstrong RA: Survival in the pre-senile dementia frontotemporal lobar degeneration with TDP-43 proteinopathy: Effects of ... 43 Jiang L, Tang Y and Huang X: Brain cell apoptosis after cerebral hypoxia-ischemia in neonatal rat. Zhonghua YI XUE ZA ZHI. ... 43-46). One study demonstrated that downregulation of Bcl-2 and simultaneous upregulation of Bax and Bid activated p53 and ...
Subcellular mislocalization of G1-regulatory Cdk4/5 is thus suggestive to cause cytotoxicity similar to TDP-43 and β-amyloid in ... Perturbances in nucleo-cytoplasmic protein trafficking contribute to cellular pathology in several proteinopathies of the CNS ... or TDP-43 [1,2]. As a putative novel class of molecules involved, we recently identified disturbances in the subcellular ...
患者脳に蓄積する不溶化TDP-43のプリオン様性質. Prion-like properties of pathological insoluble TDP-43 in diseased brains. *野中 隆 / Takashi Nonaka:1 ... Brain Proteinopathy 2014. Brain Proteinopathy 2014. *Place:Room E(301). *Time:2014/9/11 17:00 - 19
Our research is centered on exploring the intricacies of neuronal vulnerability and the toxicity of non-neuronal cells in TDP- ... 43 proteinopathies, which encompass Alzheimers disease and Frontotemporal Dementia. At the core of our investigations lie ...
Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort ... one study reported APOE4 increasing the risk of impaired cognition and multiple neurodegenerative proteinopathies (Walker and ... TDP-43), such as limbic-predominant age-related TDP-43 encephalopathy (LATE) and hippocampal sclerosis (e.g., Yang et al., 2018 ... at least one TDP-43opathy appears to be unaffected by APOE4: a large meta-analysis including 4,000 amyotrophic lateral ...
... and FTD caused by TDP43 proteinopathy (FTD-TDP43). Patients with FTD-17 suffer behavioral changes and often Parkinson-like ... Vaccaro, A., Tauffenberger, A., Ash, P. E., Carlomagno, Y., Petrucelli, L., and Parker, J. A. (2012b). TDP-1/TDP-43 regulates ... Overexpression of tdp-1/TDP-43 resulted in toxicity and decreased lifespan, analogous to the phenotypes found in ALS patients ( ... TDP-1. TDP-1 controls longevity and oxidative stress in the worm by regulating the insulin pathway (Vaccaro et al., 2012b). ...
LATE - Une protéinopathie TDP-43 qui frappe après 80 ans. 02 May 2019 - Posted by admin in Français ... A proteinopathy that strikes after 80 years old.. 07 May 2019 - Posted by admin in English ... TDP-43 and ALS. Although mutations in TDP-43 are very rare, occurring in 3% of fALS and 1.5% of sALS, more than 90% of ALS ... TDP-43 and ALS. Although mutations in TDP-43 are very rare, occurring in 3% of fALS and 1.5% of sALS, more than 90% of ALS ...
TDP-43 Proteinopathies Preferred Term Term UI T749892. Date04/23/2009. LexicalTag NON. ThesaurusID NLM (2010). ... thus making these proteinopathies distinct from most other neurogenerative disorders in which protein misfolding leads to brain ... TDP-43 Proteinopathies [C10.574.950] * Amyotrophic Lateral Sclerosis [C10.574.950.050] * Frontotemporal Lobar Degeneration [ ... TDP-43 Proteinopathies [C18.452.845.800] * Amyotrophic Lateral Sclerosis [C18.452.845.800.050] * Frontotemporal Lobar ...
  • Two specific aims are proposed which will (1) determine the molecular composition of pathologic TDP-43 protein inclusions, and (2) identify the abnormalities in RNA processing due to the loss of normal nuclear TDP- 43 protein. (neurodegenerationresearch.eu)
  • Pathology in the nervous system of dementia and MND patients contains a protein called 'TDP-43', but it remains unknown how this causes disease. (edu.au)
  • In most, if not all proteinopathies, a change in the 3-dimensional folding conformation increases the tendency of a specific protein to bind to itself. (wikipedia.org)
  • Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) share overlapping genetic causes and disease symptoms, and are linked neuropathologically by the RNA binding protein TDP-43 (TAR DNA binding protein-43 kDa). (nature.com)
  • TDP-43 is a highly conserved, ubiquitously expressed, multifunctional nucleic acid-binding protein composed of two RNA recognition motifs (RRM), nuclear localization (NLS) and export signals (NES), and a carboxy-terminal glycine rich region. (nature.com)
  • In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). (nih.gov)
  • The acronym LATE stands for Limbic-predominant Age-related TDP-43 Encephalopathy: "limbic" is related to the brain areas first involved, "age-related" and the name "LATE" itself refer to the onset of disease usually in persons aged 80 or older, "TDP-43" indicates the aberrant mis-folded protein (or proteinopathy) deposits in the brain that characterize LATE, and "encephalopathy" means illness of brain. (wikipedia.org)
  • The diagnosis of LATE-NC at autopsy requires detection of pathologic TDP-43 protein deposits in the brain, especially in the amygdala and hippocampus. (wikipedia.org)
  • TDP-43 has been identified as the major pathologic protein in sporadic ALS and has also been found in the most common pathologic subtype of FTD (ie, frontotemporal lobar degeneration with ubiquitinated inclusions). (medscape.com)
  • TDP-43 is intimately linked with amyotrophic lateral sclerosis, but the mystery remains as to what the protein is normally meant to do, and what goes wrong when it mutates. (alzforum.org)
  • Two recent papers address these questions, focusing on TDP-43's stability and protein-protein interactions. (alzforum.org)
  • In PNAS online this week, researchers report that TDP-43 mutants last longer in the cell than the wild type protein, and are more likely to hook up with FUS, another protein involved in ALS. (alzforum.org)
  • TDP-43 pathology includes cytoplasmic aggregates of the normally nuclear protein. (alzforum.org)
  • TDP-43 is known to modify mRNAs, so it was no surprise to see components of the heterogenous nuclear ribonuclear (hnRNP) protein complex, as well as other RNA-binding proteins. (alzforum.org)
  • Precipitating TDP-43 pulled down less than 1 percent of the cell's FUS, and precipitating FUS similarly brought down less than 1 percent of TDP-43 protein. (alzforum.org)
  • Ling plans to examine TDP-43 stability and protein-protein interactions in neurons and patient-derived cells. (alzforum.org)
  • In one data set, mutants of a protein involved in RNA biogenesis and processing, human TAR DNA binding protein 43 (TDP-43), were expressed in S. cerevisiae . (frontiersin.org)
  • 1 , 2 The discovery of the central role of the protein TDP-43, encoded by TARDBP , in ALS was a breakthrough in ALS research. (nature.com)
  • Transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein encoded by the TARDBP gene that is involved in RNA splicing, trafficking, stabilization, and thus, the regulation of gene expression. (biomedcentral.com)
  • TDP-43 is a 43 kDa heterogeneous nuclear ribonuclear protein (hnRNP) composed of 414 amino acids and is encoded by the TARDBP gene located on chromosome 1 (1p36.22) [ 14 ]. (biomedcentral.com)
  • Among those 13 different types of gene mutation that causes FALS, mutation in Transactive response DNA binding Protein 43kDa (TDP-43) gene is seen in approximately 4% of FALS and 2% of SALS (7). (fromemuseum.org)
  • Transactive response DNA binding protein 43kDa (TDP-43) is a DNA/RNA-binding protein encode by the TARDBP gene on chromosome 1. (fromemuseum.org)
  • TDP-43 is an ubiquitously expressed nuclear protein capable of shutting between the nucleus and cytoplasm (8). (fromemuseum.org)
  • One such mechanism may be defective nuclear import of TDP-43 protein, as a disruption of its nuclear localization signal leads to mislocalization and aggregation of TDP-43 in the cytoplasm. (crick.ac.uk)
  • In order to explore the factors that regulate the nuclear import of TDP-43, we used a small interfering RNA library to silence 82 proteins involved in nuclear transport and found that knockdowns of karyopherin-beta1 and cellular apoptosis susceptibility protein resulted in marked cytoplasmic accumulation of TDP-43. (crick.ac.uk)
  • Analysis of the expression of chosen nuclear import factors in post-mortem brain samples from patients with TDP-43 positive frontotemporal lobar degeneration, and spinal cord samples from patients with amyotrophic lateral sclerosis, revealed a considerable reduction in expression of cellular apoptosis susceptibility protein in frontotemporal lobar degeneration. (crick.ac.uk)
  • We propose that cellular apoptosis susceptibility protein associated defective nuclear transport may play a mechanistic role in the pathogenesis of the TDP-43 positive frontotemporal lobar degeneration. (crick.ac.uk)
  • PIKFYVE is a novel therapeutic target for ALS and may also be relevant for treating additional TDP-43 proteinopathies such as Frontotemporal Dementia (FTD). (countyenews.com)
  • TDP-43 pathology was absent. (sens.org)
  • AD patients with TDP-43 pathology have increased severity of cognitive impairment compared to those without TDP-43 pathology. (biomedcentral.com)
  • Furthermore, the most common genetic risk factor for AD, apolipoprotein E4 ( APOE4 ), is associated with increased frequency of TDP-43 pathology. (biomedcentral.com)
  • These findings provide strong evidence that TDP-43 pathology is an integral part of multiple neurodegenerative conditions, including AD. (biomedcentral.com)
  • We emphasize the need for studies on the mechanisms that lead to TDP-43 pathology, especially in the setting of age-related disorders such as AD. (biomedcentral.com)
  • Although evidence suggest that there is a definitive association between ALS and TDP-43, above observations make it confusing to whether TDP-43 pathology is causative or a secondary response in this disease. (fromemuseum.org)
  • Studies done to unravel if TDP-43 is pathology or secondary response to ALS have come with conflicting result. (fromemuseum.org)
  • Cytoplasmic inclusion bodies containing phosphorylated and truncated forms of TDP-43 are hallmarks of amyotrophic lateral sclerosis (ALS) and a subset of frontotemporal lobar degeneration (FTLD). (biomedcentral.com)
  • Interestingly, TDP-43 positive cytoplasmic inclusion are found in almost all ALS patient along with other neurodegenerative disease (16). (fromemuseum.org)
  • Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS. (nature.com)
  • This project will therefore explore the effects of TDP-43 malfunction, which will provide insight into potential therapeutic strategies. (edu.au)
  • Here we have employed a primary rodent neuronal culture model to study the cellular effects of TDP-43 dysfunction in hippocampal and cortical neurons. (nature.com)
  • In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. (nature.com)
  • The connection between ALS and FTD has been further confirmed at the molecular level by the identification of TDP-43 as the major component of ubiquitin-positive inclusions in both ALS and the most common pathological form of FTD 7 , 8 . (nature.com)
  • Data now suggest that delocalization, accumulation, and ubiquitination of TDP-43 in the cytoplasm of motor neurons are early dysfunctions in the cascade of the events leading to motor neuron degeneration in ALS. (medscape.com)
  • The interaction is most likely an early event" in disease, Ling speculated, leading up to later stages where TDP-43 and FUS, normally nuclear proteins, are mislocalized and aggregated in the cytoplasm. (alzforum.org)
  • Analysis of TDP-43 in the brain and spinal cord of ALS patients reveled that TDP-43 is pathologically modified and redistribution to the cytoplasm, which is accompanied by loss of normal nuclear function and a toxic gain-of-function in the cytoplasm (14,15). (fromemuseum.org)
  • The mislocalization of TDP-43 into cytoplasm is believed to be cause of neuron loss in ALS patients. (fromemuseum.org)
  • TDP-43 is predominantly located in the nucleus, however, in disease it mislocalizes to the cytoplasm where it aggregates to form hallmark pathological inclusions. (crick.ac.uk)
  • The authors report that TDP-43 possesses a prion-like domain that allows it to bind polyglutamate inclusions, such as those found in Huntington disease. (alzforum.org)
  • Additionally, TDP-43 inclusions have been found in up to 57% of Alzheimer's disease (AD) cases, most often in a limbic distribution, with or without hippocampal sclerosis. (biomedcentral.com)
  • We believe AS-202 has the potential to address this unmet need through its unique dual mechanism of action, which addresses TDP-43 aggregation and improves TDP-43 function, the pathological hallmark of ALS and other TDP-43 proteinopathies including certain forms of dementia. (countyenews.com)
  • In this review, we focus on TDP-43 in aging and AD from clinical, pathological, and basic research perspectives. (biomedcentral.com)
  • Specifically, aggregation was found to be associated with increased cell fitness in the case of TDP-43 mutations, as it protects the host from aberrant interactions. (frontiersin.org)
  • However, the cellular and molecular mechanisms by which dysfunction of TDP-43 contributes to disease pathogenesis and progression remain unclear. (nature.com)
  • Environmental exposure to metals and the development of tauopathies, synucleinopathies, and TDP-43 proteinopathies: A systematic evidence map protocol. (bvsalud.org)
  • In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. (nih.gov)
  • This study determined the prevalence and distribution of neurodegenerative proteinopathies in patients with infection-induced acute or chronic inflammation associated with herpes simplex virus (HSV) encephalitis (n = 13) and neurosyphilis (n = 23). (sens.org)
  • 2022). Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy. (upenn.edu)
  • Although the precise cellular function of TDP-43 is unknown, TDP-43 has been implicated in regulating of gene transcription (9),alternative exon splicing (10) and mRNA stability (11). (fromemuseum.org)
  • Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies. (nih.gov)
  • Although aberrant dendritic morphology has been reported in non-TDP-43 mouse models of ALS and in human ALS patients, this phenotype is largely unexplored with regards to TDP-43. (nature.com)
  • Under normal physiological conditions, TDP-43 resides predominantly in the nucleus where it involved in gene expression. (fromemuseum.org)
  • [3] The proteinopathies include such diseases as Creutzfeldt-Jakob disease and other prion diseases , Alzheimer's disease , Parkinson's disease , amyloidosis , multiple system atrophy , and a wide range of other disorders. (wikipedia.org)
  • Despite the numerous, well-described functions and interactions of TDP-43, it is not well understood exactly which TDP-43-dependent cellular processes become defective in ALS/FTD and contribute to disease etiology. (nature.com)
  • Ling examined three disease-associated TDP-43 mutants-G298S, Q331K, and M337V-as well as wild-type constructs. (alzforum.org)
  • Researchers have long sought to connect TDP-43 and FUS in a common pathway leading to neurodegenerative disease, so Ling and colleagues pursued this particular interaction further. (alzforum.org)
  • Various other neurodegenerative disease-related proteins, including amyloid-β, tau and TDP-43, can also propagate through neural networks in a similar manner. (elifesciences.org)
  • The precise role of TDP-43 in ALS and other neurodegenerative disease is not well known and needs further evaluation. (fromemuseum.org)
  • We show that manipulation of TDP-43 expression levels causes significant defects in dendritic branching and outgrowth, without an immediate effect on cell viability. (nature.com)
  • The effect on dendritic morphology is dependent on the RNA-binding ability of TDP-43. (nature.com)
  • Thus, this model system will be useful in identifying pathways downstream of TDP-43 that mediate dendritic arborization, which may provide potential new avenues for therapeutic intervention in ALS/FTD. (nature.com)
  • but it is wild-type TDP-43 that is deposited in the vast majority of TDP-43 proteinopathies, implicating other unknown factors for its mislocalization and aggregation. (crick.ac.uk)
  • 2023). C-terminal frameshift variant of TDP-43 with pronounced aggregation-propensity causes rimmed vacuole myopathy but not ALS/FTD. (upenn.edu)
  • However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. (nature.com)
  • Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. (nature.com)
  • The second study, posted online in the Journal of Biological Chemistry on June 16, suggests one possible mechanism by which TDP-43 might bind other proteins. (alzforum.org)
  • They pulse-labeled growing cells with radioactive methionine and cysteine to tag newly translated proteins, then followed TDP-43 radioactivity over time. (alzforum.org)
  • However, the researchers did not expect the second set of proteins attached to TDP-43: elements of the Drosha microprocessing complex that refines microRNA (miRNA). (alzforum.org)
  • I think it is a very tempting idea that it [TDP-43] is sitting on both pathways…to regulate gene expression," Ling said. (alzforum.org)
  • In addition, Ling and colleagues' paper describes one possible way TDP-43 and FUS pathways could intersect. (alzforum.org)
  • In some cases, TDP-43 deposits are also found in neurons with neurofibrillary tangles. (biomedcentral.com)
  • These studies will further our understanding of TDP-43 proteinopathies by using highly innovative techniques to study human brain tissue with advanced molecular techniques. (neurodegenerationresearch.eu)
  • Moreover, the present of TDP-43 in inclusion body of another neurodegenerative has been a mystery. (fromemuseum.org)
  • A longer half-life could dramatically affect TDP-43 biology, which is poorly characterized. (alzforum.org)
  • Here, we review the biology and pathobiology of TDP-43 with a focus on its role in AD. (biomedcentral.com)
  • Perhaps, they write, TDP-43 may help bridge the two (hnRNP and miRNA) complexes, though it is not yet clear what function this might have. (alzforum.org)
  • For the work described in PNAS, first author Shuo-Chien Ling, in the laboratory of Don Cleveland at the University of California in San Diego, led the effort to distinguish the actions of wild-type and mutant TDP-43. (alzforum.org)
  • This paper is one of the first to show real differences between wild-type and mutant TDP-43, said Robert Baloh, Washington University School of Medicine in St. Louis, Missouri. (alzforum.org)
  • Baloh, along with first author Rodrigo Fuentealba, led an inquiry into the prion-like region of TDP-43, which they describe in the recent Journal of Biological Chemistry paper. (alzforum.org)
  • Theoretically, he suggested, the same might happen in sporadic ALS, if some other mechanism enhanced the stability of wild-type TDP-43. (alzforum.org)
  • In wild-type fibroblasts, TDP-43 has a four-hour half-life, but this rises to 11 hours in cells from a person carrying the G298S mutation. (alzforum.org)
  • The mutants lasted two to four times longer than wild-type TDP-43 does, suggesting they are more resistant to degradation. (alzforum.org)