Abstract
Cells have developed elaborate quality-control mechanisms for proteins and organelles to maintain cellular homeostasis. Such quality-control mechanisms are maintained by conformational folding via molecular chaperones and by degradation through the ubiquitin-proteasome or autophagy-lysosome system. Accumulating evidence suggests that impaired autophagy contributes to the accumulation of intracellular inclusion bodies consisting of misfolded proteins, which is a hallmark of most neurodegenerative diseases. In addition, genetic mutations in core autophagy-related genes have been reported to be linked to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Conversely, the pathogenic proteins, such as amyloid β and α-synuclein, are detrimental to the autophagy pathway. Here, we review the recent advances in understanding the relationship between autophagic defects and the pathogenesis of neurodegenerative diseases and suggest autophagy induction as a promising strategy for the treatment of these conditions.
Highlights
Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Korea; Department of Pharmacology, College of Medicine, Inha University, Incheon 22212, Korea
The precise mechanisms of autophagosome closure are still not clear, accumulating evidence suggests that ATG2, VPS21, and the endosomal sorting complexes required for transport (ESCRT) complex play a role in autophagosome closure [35,37,38,39]
Inherited neurodegenerative diseases are caused by mutations in various genes, the accumulation of protein aggregates is a common characteristic they share
Summary
Autophagy is an evolutionary conserved intracellular degradation process. Mammals present three types of autophagic processes according to the adopted mechanism of cargo transport into lysosomes: chaperone-mediated autophagy, microautophagy, and macroautophagy, hereafter referred to as autophagy. Unnecessary or misfolded proteins and damaged subcellular organelles are engulfed by autophagy-specific double membrane-bound vesicles, called autophagosomes, and delivered to the lysosomes for breakdown. Autophagy occurs at a low basal level under inhibition by the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of autophagy, to sustain cellular homeostasis. Upon various types of cellular stress, such as nutrient deprivation, growth factor withdrawal, or hypoxia, autophagy is released from mTORC1 inhibition and is highly upregulated to meet high energy demands
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