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)

Mutation in the CHMP2B gene has been implicated in frontotemporal dementia. The authors screened CHMP2B in patients with ALS and several cohorts of control samples. They identified mutations (Q206H; I29V) in two patients with non-SOD1 ALS. Neuropathology of the Q206H case showed lower motor neuron predominant disease with ubiquitylated inclusions in motor neurons. Antibodies to p62 (sequestosome 1) showed novel oligodendroglial inclusions in the motor cortex.
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PMID:ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). 1680 8

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease classically defined by the impairment of the voluntary motor system and ubiquitin-positive intraneuronal aggregates in anterior horn cells. Frontotemporal dementia (FTD) is a common form of neurodegenerative dementia and presents with personality change associated in a significant subgroup of patients with cortical ubiquitin-only neuropathology (FTD-U). Careful study of ALS as well as FTD patient cohorts suggests clinical as well as pathological overlap of ALS with FTD. The idea that this reflects a shared pathogenesis has received strong support from the identification of new genetic loci on chromosome 9p and of mutations in specific genes (CHMP2B and DCN1) in families with co-segregation of ALS and FTD. The identification of two further genetic causes of FTD-U with (rare) ALS (PGRN) or without ALS (VCP) also provides a starting point for exploring the pathways associated with ubiquitin-mediated protein mishandling in FTD-U and ALS. Pure ALS, through ALS with cognitive impairment and ALS-FTD to pure FTD-U, may represent a continuous spectrum of ubiquitin-associated neurodegenerative disease.
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PMID:Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease. 1698 82

Work done over the past decade has led to a molecular understanding of frontotemporal lobar degeneration (FTLD), a deadly disease that afflicts patients in mid-life. It is a common cause of dementia, second only to Alzheimer's disease in the population below 65 years of age. Neuroanatomical and neurobiological substrates have been identified for the three major subtypes of FTLD and these discoveries have broadened the FTLD spectrum to include amyotrophic lateral sclerosis (ALS). Mutations in MAPT were found to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), a familial disorder with filamentous tau inclusions in nerve cells and glial cells. FTDP-17 can result in clinical syndromes that closely resemble progressive supranuclear palsy, corticobasal degeneration and Pick's disease. More recently, mutations in three genes (VCP, CHMP2B and PGRN) have been found to cause FTLD with ubiquitin-positive, tau-negative neuronal inclusions (FTLD-U). They explain a large proportion of inherited FTLD-U. It remains to be seen whether dementia lacking distinctive histopathology (DLDH) constitutes a third disease category, as many of these cases are now being reclassified as FTLD-U. Recently, TAR DNA-binding protein-43 (TDP-43) has been identified as a key protein of the ubiquitin inclusions of FTLD-U and ALS. Thus, for familial forms of FTLD and related disorders, we now know the primary etiologies and accumulating proteins. These findings are pivotal for dissecting the pathways by which different etiologies lead to the varied clinicopathological presentations of FTLD.
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PMID:Frontotemporal lobar degeneration: current concepts in the light of recent advances. 1749 44

Frontotemporal lobar degeneration (FTLD) is a common form of dementia that usually afflicts patients in their mid-life. Clinically, patients with FTLD present with changes in behavior and/or language dysfunction. According to their underlying neuropathological substrate, these neurodegenerative conditions can now be classified into two main groups: those with tau pathology (tauopathies), and those without tau pathology. In the majority of nontauopathy disorders the recently identified TAR DNA-binding protein-43 (TDP-43) is found as the major inclusion protein (TDP-43 proteinopathies), and TDP-43 is also present in motor neuron inclusions of amyotrophic lateral sclerosis. Presently, mutations in 4 genes (MAPT, PGRN, VCP, CHMP2B) are known to cause diverse types of FTLD pathology. Here, we summarize the recent neuropathological and genetic advances in FTLD research.
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PMID:Pathology and genetics of frontotemporal lobar degeneration: an update. 1770 95

The endosomal sorting complexes required for transport (ESCRTs) are required to sort integral membrane proteins into intralumenal vesicles of the multivesicular body (MVB). Mutations in the ESCRT-III subunit CHMP2B were recently associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), neurodegenerative diseases characterized by abnormal ubiquitin-positive protein deposits in affected neurons. We show here that autophagic degradation is inhibited in cells depleted of ESCRT subunits and in cells expressing CHMP2B mutants, leading to accumulation of protein aggregates containing ubiquitinated proteins, p62 and Alfy. Moreover, we find that functional MVBs are required for clearance of TDP-43 (identified as the major ubiquitinated protein in ALS and frontotemporal lobar degeneration with ubiquitin deposits), and of expanded polyglutamine aggregates associated with Huntington's disease. Together, our data indicate that efficient autophagic degradation requires functional MVBs and provide a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.
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PMID:Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. 1798 23

Mutations in the endosomal sorting complexes required for transport (ESCRT)-III subunit CHMP2B are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both human neurodegenerative diseases characterized by accumulation of ubiquitinated proteins aggregates in affected neurons. The ESCRT proteins are known to be involved in diverse cellular processes such as mRNA transport, cytokinesis, transcriptional regulation and sorting of transmembrane proteins into the inner vesicles of the multivesicular body (MVB) during endocytosis. It was until recently not clear how ESCRT function may be involved in neurodegeneration. New findings in mammalian cells and in Drosophila melanogaster show that functional ESCRTs are required for efficient fusion of autophagic vesicles with the endocytic pathway and for degradation of autophagic cargo. Moreover, defective ESCRT function led to the accumulation of cytoplasmic protein aggregates containing ubiquitin, p62/Sequestosome-1 and TAR DNA binding protein 43 (TDP-43). Using cellular and Drosophila models for Huntington's disease it was also shown that reduced ESCRT levels inhibit clearance of expanded polyglutamine aggregates and aggravate their neurotoxic effect. These data indicate that efficient autophagic degradation requires functional MVBs and provides a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.
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PMID:ESCRT functions in autophagy and associated disease. 1841 46

To clarify the genetic background of amyotrophic lateral sclerosis (ALS)/parkinsonism-dementia complex (PDC) of the Kii peninsula, Japan (Kii ALS/PDC), we performed extended mutation analyses of three patients with pathologically diagnosed Kii ALS/PDC. Direct sequencing analyses were performed in 19 genes, including ALS/frontotemporal lobar degeneration (FTLD)-related genes (SOD2, SOD3, ALS2/alsin, SMN1, PGRN, ANG, VEGF, VCP, VAPB, DCTN1, CHMP2B, and TARDBP or TDP-43), tauopathy-related gene (GSK3beta), and parkinsonism-related genes (alpha-synuclein, LRRK2, parkin, DJ-1, PINK1, and ATP13A2). Gene dosage analyses were conducted in screening of MAPT, alpha-synuclein, TDP-43 (or TARDBP), GSK3beta, and parkin. We found no mutation in the 19 genes. We found a homozygous nonsynonymous SNP (ALS2/alsin V368M) shared by all the three patients. Gene dosage was normal in MAPT, alpha-synuclein, TDP-43, GSK3beta, and parkin. The present findings, together with a previous negative study on MAPT and SOD1 mutation, further elucidated the lack of causative mutations in all exons, exon-intron boundaries, or some rearrangements of the reported major causative or susceptible genes related to ALS, FTLD, parkinsonism, synucleinopathy, TDP-43 proteinopathy, and tauopathy. However, the familial aggregation and lack of any environment factors suggest that Kii ALS/PDC is caused by other yet unidentified genetic factors.
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PMID:Mutation analyses in amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula, Japan. 1875 52

The cause of familial amyotrophic lateral sclerosis (FALS) has been attributed to mutations in several genes. The authors analyzed these genes, including SOD1, FUS, VAPB, ANG, TDP-43, FIG4, and CHMP2B, in a cohort of 15 index patients of Han Chinese descent with adult-onset FALS. Seven different mutations in eight patients, including three in SOD1 (G85R, T137R, and G138E), two in exon 15 of FUS (H517D and R521H), and two in exon 6 of TARDBP (M337V and N378D) were identified. Among them, T137R SOD1, G138E SOD1, H517D FUS, and N378D TARDBP were novel. No mutation was found in VAPB, ANG, FIG4, or CHMP2B genes. Mutations in SOD1, FUS, and TARDBP account for 20%, 13.3%, and 20% of FALS, respectively. This study defined the distribution and frequency of mutations of FALS in a Taiwanese Han Chinese population, which not only broadens the spectrum of the mutations causing FALS, but also further highlights the importance of FUS and TARDBP in the pathogenesis of amyotrophic lateral sclerosis (ALS).
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PMID:FUS, TARDBP, and SOD1 mutations in a Taiwanese cohort with familial ALS. 2047 25

Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for disease-specific therapeutic trials in the future.
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PMID:Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. 2097 53

Research into amyotrophic lateral sclerosis (ALS) has been stimulated by a series of genetic and molecular pathology discoveries. The hallmark neuronal cytoplasmic inclusions of sporadic ALS (sALS) predominantly comprise a nuclear RNA processing protein, TDP-43 encoded by the gene TARDBP, a discovery that emerged from high throughput analysis of human brain tissue from patients with frontotemporal dementia (FTD) who share a common molecular pathology with ALS. The link between RNA processing and ALS was further strengthened by the discovery that another genetic locus linking familial ALS (fALS) and FTD was due to mutation of the fused in sarcoma (FUS) gene. Of potentially even greater importance it emerges that TDP-43 accumulation and inclusion formation characterises not only most sALS cases but also those that arise from mutations in several genes including TARDBP (predominantly ALS cases) itself, C9ORF72 (ALS and FTD cases), progranulin (predominantly FTD phenotypes), VAPB (predominantly ALS cases) and in some ALS cases with rare genetic variants of uncertain pathogenicity (CHMP2B). "TDP-proteinopathy" therefore now represents a final common pathology associated with changes in multiple genes and opens the possibility of research by triangulation towards key common upstream molecular events. It also delivers final proof of the hypothesis that ALS and most FTD cases are disorders within a common pathology expressed as a clinico-anatomical spectrum. The emergence of TDP-proteinopathy also confirms the view that glial pathology is a crucial facet in this class of neurodegeneration, adding to the established view of non-nerve cell autonomous degeneration of the motor system from previous research on SOD1 fALS. Future research into the mechanisms of TDP-43 and FUS-related neurodegeneration, taking into account the major component of glial pathology now revealed in those disorders will significantly accelerate new discoveries in this field, including target identification for new therapy.
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PMID:Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. 2210 41


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