Autophagy, a guardian against neurodegeneration

Abstract

Autophagy is an intracellular degradation process responsible for the clearance of most long-lived proteins and organelles. Cytoplasmic components are enclosed by double-membrane autophagosomes, which subsequently fuse with lysosomes for degradation. Autophagy dysfunction may contribute to the pathology of various neurodegenerative disorders, which manifest abnormal protein accumulation. As autophagy induction enhances the clearance of aggregate-prone intracytoplasmic proteins that cause neurodegeneration (like mutant huntingtin, tau and ataxin 3) and confers cytoprotective roles in cell and animal models, upregulating autophagy may be a tractable therapeutic strategy for diseases caused by such proteins. Here, we will review the molecular machinery of autophagy and its role in neurodegenerative diseases. Drugs and associated signalling pathways that may be targeted for pharmacological induction of autophagy will also be discussed.

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

“…The lysosome is the major cellular compartment for protein degradation (De Duve and Wattiaux, 1966), and within the lysosome the degradation of proteins occurs through three distinct pathways: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). The lysosomal autophagy process destroys misfolded, long-lived or aggregate-prone proteins in the cell and, in doing so, confers a cytoprotective role (García-Arencibia et al, 2010). Defective autophagy and/or depletion of lysosomes have been implicated in PD pathogenesis (Cuervo et al, 2004;; Alvarez-Erviti et al, 2010;; Dehay et al, 2010;; Wong and Cuervo, 2010) and in a Gaucher mouse model (Cullen et al, 2011).…”

Vps34p Is Required for the Decline of Extracellular Fructose-1,6-bisphosphatase in the Vacuole Import and Degradation Pathway

“…Under nitrogen starvation conditions in S. cerevisiae, a nonselective macroautophagic pathway targets proteins and organelles to the vacuole for degradation (15)(16)(17)(18)(19). Our laboratory studies a selective autophagic pathway that delivers specific cytosolic proteins to the vacuole in response to nutrient replenishment (13).…”

Vid30 is required for the association of Vid vesicles and actin patches in the vacuole import and degradation pathway

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] Furthermore, disrupted autophagy has been associated with diseases such as cancer, neurodegeneration and aging. 1,3,4,15,16 Multiple autophagy pathways including macroautophagy, microautophagy and chaperone-mediated autophagy have been characterized. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] The macroautophagy pathway is conserved from yeast to human.…”

“…1,3,4,15,16 Multiple autophagy pathways including macroautophagy, microautophagy and chaperone-mediated autophagy have been characterized. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] The macroautophagy pathway is conserved from yeast to human. It is induced in Saccharomyces cerevisiae that have been starved of nitrogen.…”

“…In animal models of aggregate prone diseases, rapamycin clears large aggregates and improves the performance of the affected animals. 4,[21][22][23][24][25] Hence, activation of the nonselective macroautophagy pathway may be beneficial for treating patients with aggregate-prone diseases.…”