title: Amyotrophic lateral sclerosis: Problems and prospects.
abstract: Amyotrophic lateral sclerosis (ALS) is a lethal degenerative disorder of motoneurons, which may occur concurrently with frontotemporal dementia. Genetic analyses of the ∼10% of ALS cases that are dominantly inherited provide insight into ALS pathobiology. Two broad themes are evident. One, prompted by investigations of the SOD1 gene, is that conformational instability of proteins triggers downstream neurotoxic processes. The second, from studies of the TDP43, FUS, and C9orf72 genes, is that perturbations of RNA processing can be highly adverse in motoneurons. Several investigations support the concept that non-neuronal cells (microglia, astroglia, oligodendroglia) participate in the degenerative process in ALS. Recent data also emphasize the importance of molecular events in the axon and distal motoneuron terminals. Only 1 compound, riluzole, is approved by the US Food and Drug Administration for ALS; several therapies are in clinical trials, including 2 mesenchymal stem cell trials. The challenges and unmet needs in ALS emphasize the importance of new research directions: high-throughput sequencing of large DNA sets of familial and sporadic ALS, which will define scores of candidate ALS genes and pathways and facilitate studies of epistasis and epigenetics; infrastructures for candidate gene validation, including in vitro and in vivo modeling; valid biomarkers that elucidate causative molecular events and accelerate clinical trials; and in the long term, methods to identify environmental toxins. The unprecedented intensity of research in ALS and the advent of extraordinary technologies (rapid, inexpensive DNA sequencing; stem cell production from skin-derived fibroblasts; silencing of miscreant mutant genes) bode well for discovery of innovative ALS therapies.
authors.affiliation: Babraham Institute, Cambridge, United Kingdom; Department of Neurology, University of Massachusetts Medical School, Worcester, MA; Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Jemeen
authors.initials: J
authors.lastname: Sreedharan
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D005820:Genetic Testing; D015316:Genetic Therapy; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism
chemical_list: D034702:RNA-Binding Protein FUS; D013482:Superoxide Dismutase