title: Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis.
abstract: The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.
authors.affiliation: Department of Neurology, University of Michigan, 109 Zina Pitcher Place, 5015 Biomedical Sciences Research Building, SSPC 2200, Ann Arbor, MI, 48109, USA, sbarmada@umich.edu.
authors.forename: Sami J
authors.initials: SJ
authors.lastname: Barmada
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics*; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology; D012313:RNA / Q000235:genetics* / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D035683:MicroRNAs; D034702:RNA-Binding Protein FUS; C000598624:TARDBP protein, human; D012313:RNA