AIMS Molecular Science, 2016, 3(2): 246-268. doi: 10.3934/molsci.2016.2.246 Review Special Issues

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Mislocalization, aggregation formation and defect in proteolysis in ALS

Atsushi Tsubota, Hidenori Ichijo, Kengo Homma

Laboratory of Cell Signaling, Graduate school of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan

Received: , Accepted: , Published:

Special Issues: Cell Signalling and Neuronal Cell Death

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motoneuron degeneration. The features observed in ALS are the mislocalization and aggregation of proteins in the affected motoneurons. The mutants of Cu/Zn superoxide dismutase (SOD1) or TAR DNA binding protein (TDP-43) that cause ALS have been reported to localize aberrantly. These aggregations contain the products of ALS causative genes, including SOD1 or TDP-43. Notably, TDP-43-positive aggregations have been identified even in sporadic ALS cases, indicating the importance of aggregate formation in the pathogenesis of ALS. Various proteins other than ALS causative gene products are also included in these aggregates. It is thought that the genetic mutation-induced conformational changes of proteins cause the aberrant redistribution and formation of aggregates, resulting in a loss of function or a gain of neuronal toxicity through the undesired interactions. Additionally, valosin-containing protein (VCP), ubiquilin2 (UBQLN2) and optineurin (OPTN), which are related to the proteolysis system, have also been identified as causative genes in ALS. These facts suggest that the aberrant protein homeostasis mediated by mislocalization, aggregate formation, or defects in the proteolysis system are the underlying causes of neuronal toxicity in ALS. Here, we focus on the impaired protein homeostasis observed in ALS to discuss the potential for motoneuron toxicity.

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