Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Frontotemporal lobar degeneration (FTLD) with inclusion body myopathy and Paget disease of bone is a rare, autosomal dominant disorder caused by mutations in the VCP (valosin-containing protein) gene. The disease is characterized neuropathologically by frontal and temporal lobar atrophy, neuron loss and gliosis, and ubiquitin-positive inclusions (FTLD-U), which are distinct from those seen in other sporadic and familial FTLD-U entities. The major component of the ubiquitinated inclusions of FTLD with VCP mutation is TDP-43 (TAR DNA-binding protein of 43 kDa). TDP-43 proteinopathy links sporadic amyotrophic lateral sclerosis, sporadic FTLD-U, and most familial forms of FTLD-U. Understanding the relationship between individual gene defects and pathologic TDP-43 will facilitate the characterization of the mechanisms leading to neurodegeneration. Using cell culture models, we have investigated the role of mutant VCP in intracellular trafficking, proteasomal function, and cell death and demonstrate that mutations in the VCP gene 1) alter localization of TDP-43 between the nucleus and cytosol, 2) decrease proteasome activity, 3) induce endoplasmic reticulum stress, 4) increase markers of apoptosis, and 5) impair cell viability. These results suggest that VCP mutation-induced neurodegeneration is mediated by several mechanisms.
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PMID:VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death. 1923 41

Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to alpha-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.
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PMID:Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. 1927 Nov 5

Patients presenting with left-sided FTLD syndromes sometimes develop a new preoccupation with art, greater attention to visual stimuli, and increased visual creativity. We describe the case of a 53-year-old, right-handed man with a history of bipolar disorder who presented with language and behavior impairments characteristic of FTLD, then developed motor symptoms consistent with a second diagnosis of amyotrophic lateral sclerosis. Though the patient had never created visual art before, he developed a compulsion for painting beginning at the earliest stages of his disease, and continued producing art daily until he could no longer lift a paintbrush because of his motor deficits. Upon autopsy, he was found to have ubiquitin and TDP43-positive inclusions with MND pathology. This case study details the patient's longitudinal neuropsychological, emotional, behavioral, and motor symptoms, along with structural imaging, neurologic, and neuropathologic findings. Multiple examples of the patient's art are depicted throughout all stages of his illness, and the possible cognitive, behavioral, and neurologic correlates of his new-onset visual artistry are discussed.
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PMID:A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. 1927 73

Mutations in TDP-43, a DNA/RNA-binding protein, cause an inherited form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Two recent studies (Kwiatkowski et al., 2009; Vance et al., 2009) now report that mutations in FUS/TLS, another DNA/RNA-binding protein, also trigger premature degeneration of motor neurons. TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as a key event in ALS pathogenesis.
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PMID:Rethinking ALS: the FUS about TDP-43. 1930 44

TAR DNA binding protein (TDP-43) is the pathologic substrate of neuronal and glial aggregates in amyotrophic lateral sclerosis (ALS). Pathologic TDP-43 is hyperphosphorylated and cleaved to generate abnormal protein species that accumulate in the cytoplasm. To assess the hypothesis of TDP-43 pathology as a systemic disorder in ALS we analysed the immunohistochemical and biochemical profile of TDP-43 in muscle biopsies of 30 ALS patients and 30 controls. In all ALS muscle biopsies we observed that TDP-43 was constantly present in an intranuclear localization and TDP-43 Western blotting showed only a 43-KDa band as controls. Our results suggest that TDP-43 pathology is probably confined to the central nervous system in ALS.
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PMID:TDP-43 in skeletal muscle of patients affected with amyotrophic lateral sclerosis. 1930 41

The identification of TDP-43 as the major component of the pathologic inclusions in most forms of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein under these conditions. Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies, have increased our knowledge about the spectrum of pathological changes associated with FTLD-U and ALS and moreover, facilitated the neuropathological routine diagnosis of these conditions. This review summarizes the recent advances in our understanding on the molecular neuropathology and pathobiology of TDP-43 in FTLD and ALS.
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PMID:Molecular neuropathology of TDP-43 proteinopathies. 1933 44

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder consisting of progressive loss of motor neurons. TDP-43 has been identified as a component of ubiquitin-immunoreactive inclusions of motor neurons in ALS. We focused on the diffuse cytoplasmic TDP-43 immunoreactivity in ALS neurons, and quantitatively assessed it in comparison with skein/round TDP-43 and ubiquitin immunostaining in motor neurons of 30 sporadic ALS cases. The percentage of spinal motor neurons with cytoplasmic TDP-43 immunoreactivity was higher than that of ubiquitin-immunoreactive ones. The percentage of TDP-43-positive motor neurons was independent of neuron counts in anterior horns, while the percentage of ubiquitinated neurons was inversely correlated. Aiming to define the cytosolic localization of TDP-43, the immunoblot analysis of spinal cord and frontal cortex showed that full-length TDP-43, the 45 kDa form and ubiquitinated TDP-43 are found in the soluble inclusion-free fraction. The present data 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, preceding the formation of insoluble inclusion bodies. Being cytoplasmic accumulation an ongoing event during the course of the illness, a therapeutic approach to this incurable disease can be envisaged.
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PMID:TDP-43 redistribution is an early event in sporadic amyotrophic lateral sclerosis. 1933 76

Intra- and/or extracellular proteinaceous inclusions in the brain tissue are characteristic pathological markers of many neurodegenerative diseases. Tau protein in neurofibrillary tangles and beta-amyloid in senile plaques are associated with Alzheimer's disease. Tau is associated with various neurological conditions, which are collectively referred to as tauopathies. Alpha-synucleinopathy is a term that collectively refers to a set of diseases in which neurodegeneration is accompanied by intracellular accumulation of alpha-synuclein in neurons or glial cells. Recently, TDP-43 has been identified as a major disease protein in the ubiquitinated inclusions in deseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration with tau-negative, ubiquitin-positive inclusions. Thus, these neurodegenerative disorders comprise a new disease class, namely, TDP-43 proteinopathy. In this article, we review the present understanding of histopathological features of basal ganglia lesions in protein conformation disorders, including tauopathy, alpha-synucleinopathy, and TDP-43 proteinopathy.
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PMID:[Pathology of basal ganglia in neurodegenerative diseases]. 1937 13

Pathological modifications in the highly conserved and ubiquitously expressed heterogeneous ribonucleoprotein TDP-43 were recently associated to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a late-onset disorder that affects predominantly motoneurons [Neumann, M. et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133, Sreedharan, J. et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-1672, Kabashi, E. et al. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572-574]. However, the function of TDP-43 in vivo is unknown and a possible direct role in neurodegeneration remains speculative. Here, we report that flies lacking Drosophila TDP-43 appeared externally normal but presented deficient locomotive behaviors, reduced life span and anatomical defects at the neuromuscular junctions. These phenotypes were rescued by expression of the human protein in a restricted group of neurons including motoneurons. Our results demonstrate the role of this protein in vivo and suggest an alternative explanation to ALS pathogenesis that may be more due to the lack of TDP 43 function than to the toxicity of the aggregates.
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PMID:Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. 1937 45

Previous evidence demonstrates that TAR DNA binding protein (TDP-43) mislocalization is a key pathological feature of amyotrophic lateral sclerosis (ALS). TDP-43 normally shows nuclear localization, but in CNS tissue from patients who died with ALS this protein mislocalizes to the cytoplasm. Disease specific TDP-43 species have also been reported to include hyperphosphorylated TDP-43, as well as a C-terminal fragment. Whether these abnormal TDP-43 features are present in patients with SOD1-related familial ALS (fALS), or in mutant SOD1 over-expressing transgenic mouse models of ALS remains controversial. Here we investigate TDP-43 pathology in transgenic mice expressing the G93A mutant form of SOD1. In contrast to previous reports we observe redistribution of TDP-43 to the cytoplasm of motor neurons in mutant SOD1 transgenic mice, but this is seen only in mice having advanced disease. Furthermore, we also observe rounded TDP-43 immunoreactive inclusions associated with intense ubiquitin immunoreactivity in lumbar spinal cord at end stage disease in mSOD mice. These data indicate that TDP-43 mislocalization and ubiquitination are present in end stage mSOD mice. However, we do not observe C-terminal TDP-43 fragments nor TDP-43 hyperphosphorylated species in these end stage mSOD mice. Our findings indicate that G93A mutant SOD1 transgenic mice recapitulate some key pathological, but not all biochemical hallmarks, of TDP-43 pathology previously observed in human ALS. These studies suggest motor neuron degeneration in the mutant SOD1 transgenic mice is associated with TDP-43 histopathology.
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PMID:Mislocalization of TDP-43 in the G93A mutant SOD1 transgenic mouse model of ALS. 1937 91


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