Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons associated with the abnormal aggregation of ubiquitinated proteins. The molecular mechanisms underlying the pathogenesis of ALS remain unclear, however. Autophagy is a major pathway for the elimination of protein aggregates and damaged organelles and therefore contributes to cellular homeostasis. This catabolic process begins with the formation of the double membrane-bound autophagosome that engulfs portions of the cytoplasm and subsequently fuses with a lysosome to form an autolysosome, in which lysosomal enzymes digest autophagic substrates. Defects at various stages of autophagy have been associated with pathological mutations of several ALS-linked genes including SOD1, p62, TDP-43, and optineurin, suggesting that such defects may play a causative role in the pathogenesis of this condition. In this review, we summarize the dysregulation of autophagy associated with ALS as well as potential therapeutic strategies based on modulation of the autophagic process.
Laboratory of Cell Death and Human Diseases, Department of Life Sciences, Korea University, Seoul, South Korea.
Jae Keun
JK
Lee
Department of Microbiology, Ajou University School of Medicine, 206 World cup-ro, Yeongtong-gu, Suwon 443-749, South Korea.
Jin Hee
JH
Shin
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, South Korea; Samsung Genome Institute (SGI), Samsung Medical Center, #81 Irwon-Dong Gangnam-Gu, Seoul 135-710, South Korea. Electronic address: jieun.lee@skku.edu.
Ji Eun
JE
Lee
Laboratory of Cell Death and Human Diseases, Department of Life Sciences, Korea University, Seoul, South Korea. Electronic address: ejchoi@korea.ac.kr.
Eui-Ju
EJ
Choi
Amyotrophic lateral sclerosis; Autophagosome; Autophagy; Lysosome; Neurodegeneration