title: Molecular basis of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration with unclear etiology and no effective treatment to date. ALS is, however, increasingly recognized as a multisystem disorder associated with impaired cognition. The overlap between ALS and dementia at clinical, genetic and neuropathologic levels indicates a spectrum of clinical phenotypes that may include features of frontotemporal lobar degeneration (FTLD). Most cases of ALS are sporadic (SALS), but approximately 10% of all ALS cases are familial ALS (FALS). Mutations in the Cu/Zn superoxide dismutase-1 gene (SOD-1) occur in about 20% of FALS cases. Mutations in the TAR DNA-binding protein 43 gene (TARDBP or TDP-43) may occur in 3-4% of FALS cases, and less frequently, in FTLD. Recently, mutations in the fused in sarcoma/translation in liposarcoma gene (FUS/TLS) were identified as causing about 4-5% of FALS, SALS, and FTLD cases, but not SOD-1 ALS cases, indicating a pathogenic role of FUS, together with TDP-43, in possibly all types of ALS, except for SOD-1 linked ALS. TDP-43 and FUS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. Thus, TARDBP and FUS/TLS mutations define a novel class of neurodegenerative diseases called TDP-43- and FUS-proteinopathies, in which both misfolded proteins are novel targets for the development of therapeutics in this spectrum of diseases. However, SOD-1 linked ALS may have a pathogenic pathway distinct from other types of ALS.
authors.affiliation: Institute for Medical Research and Occupational Health, Zagreb, Croatia. rajka.liscic@gmail.com
authors.forename: Rajka M
authors.initials: RM
authors.lastname: Liscic
authors.forename: Davorka
authors.initials: D
authors.lastname: Breljak
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS