title: [Molecular pathogenesis of ALS in TDP43 era].
abstract: To clarify the molecular pathogenesis of amyotrophic lateral sclerosis (ALS) associated with TAR-DNA binding protein 43 kDd (TDP-43), the quality and quantity of TDP-43 take a crucial role. Regarding to the quality of TDP-43, TDP-43 has been reported as an aggregate-prone protein. Especially the C-terminus of the TDP-43 tends to form aggregate and has prion-like domain. Interestingly the mutations in the genes, which produce proteins with prion-like domain, have been identified in several neurodegenerative disorders. These results suggest the existence of the common property in the causative proteins for neurodegenerative disorders. For the quantity of TDP-43, the adequate amount of TDP-43 is necessary for maintaining cell function and cell survival. The amount of TDP-43 is tightly regulated by TDP-43. However the mechanism for autoregulation has not been fully elucidated. For the function of TDP-43, TDP-43 locates at stress granule, GEM and associates with the large genes and introns. Thus the alteration of TDP-43 may affect the function of stress granule, GEM and RNA metabolism in several genes. Moreover a U12 type spliceosome, which is matured in GEM, is decreased in ALS. The investigation of whether these dysfunctions explain the selective pathology in ALS provides a new therapeutic strategy for ALS.
authors.affiliation: Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute, Niigata University.
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000628:therapy; D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D011328:Prions; D066329:Protein Aggregates / Q000235:genetics; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011328:Prions; D066329:Protein Aggregates; D012313:RNA