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Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Weishaupt, Jochen H.; Hyman, Tony; Dikic, Ivan

Trends in molecular medicine. Volume 22:Number 9 (2016, September); pp 769-783 -- Elsevier Science

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  • Title:
    Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
  • Author: Weishaupt, Jochen H.;
    Hyman, Tony;
    Dikic, Ivan
  • Found In: Trends in molecular medicine. Volume 22:Number 9 (2016, September); pp 769-783
  • Journal Title: Trends in molecular medicine
  • Subjects: Molecular biology--Periodicals; Pathology, Molecular--Periodicals; Physiology, Pathological--Periodicals; amyotrophic lateral sclerosis--autophagy--frontotemporal dementia--genetics--RNA granules; Dewey: 572.8
  • Rights: Licensed
  • Publication Details: Elsevier Science
  • Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative diseases in which predominantly motor neurons and cerebral cortex neurons, respectively, are affected. Several novel ALS and FTD disease genes have been recently discovered, pointing toward a few overarching pathways in ALS/FTD pathogenesis. Nevertheless, a precise picture of how various cellular processes cause neuronal death, or how different routes leading to ALS and FTD are functionally connected is just emerging. Moreover, how the most recent milestone findings in the ALS/FTD field might lead to improved diagnosis and treatment is actively being explored. We highlight some of the most exciting recent topics in the field, which could potentially facilitate the identification of further links between the pathogenic ALS/FTD pathways related to autophagy, vesicle trafficking, and RNA metabolism. Trends The link between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), described in the 19th century based on clinical observations, has been (re)discovered and confirmed by both neuropathological and genetic findings. Recent results from human genetics have revealed common functional pathways in ALS/FTD pathogenesis. Protein products of most ALS genes act in pathways regulating autophagy and vesicle trafficking, RNA metabolism, or cytoskeleton dynamics. The functional role of impaired DNA damage repair remains to be shown. Selective autophagy connects at least four different ALS/FTD genes in one putative functional pathway [ TBK1, SQSTM1/ p62, OPTN, and chromosome 9 open reading frame 72 ( C9ORF72 )]. RNA granules are regulated by liquid-phase transition involving RNA proteins with disordered, aggregation-prone protein domains. This principle provides a plausible explanation on how RNA-binding protein mutations and protein aggregation could be linked to RNA dysregulation, and subsequently, to neuronal degeneration. New genetic mouse models based on recently discovered ALS genes are currently being evaluated.
  • Identifier: System Number: ETOCvdc_100081847339.0x000001; Journal ISSN: 1471-4914; 10.1016/j.molmed.2016.07.005
  • Publication Date: 2016
  • Physical Description: Electronic
  • Shelfmark(s): 9049.666000
  • UIN: ETOCvdc_100081847339.0x000001

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