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Neurology Research International
Volume 2012, Article ID 498428, 12 pages
Review Article

Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

Asako Otomo,1,2 Lei Pan,1,2 and Shinji Hadano1,2,3

1Department of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan
2The Institute of Medical Sciences, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan
3Research Center for Brain and Nervous Diseases, Tokai University Graduate School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan

Received 24 March 2012; Accepted 14 May 2012

Academic Editor: B. R. Ott

Copyright © 2012 Asako Otomo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.