Autophagy in Parkinson's Disease

Abstract

Impaired protein homeostasis and accumulation of damaged or abnormally modified protein are common disease mechanisms in many neurodegenerative disorders, including Parkinson's disease (PD). As one of the major degradation pathways, autophagy plays a pivotal role in maintaining effective turnover of proteins and damaged organelles in cells. Several decades of research efforts led to insights into the potential contribution of impaired autophagy machinery to α-synuclein accumulation and the degeneration of dopaminergic neurons, two major features of PD pathology. In this review, we summarize recent pathological, genetic, and mechanistic findings that link defective autophagy with PD pathogenesis in human patients, animals, and cellular models and discuss current challenges in the field.

Keywords: Parkinson’s disease; chaperone-mediated autophagy; macroautophagy; mitophagy; α-synuclein.

Figure 1.. Schematic depiction of PD-related genes associated with different autophagy pathways.

A large group of genes associated with familial and sporadic PD are strongly linked to macroautophagy, chaperone-mediated autophagy, mitophagy, and downstream lysosomal function. Macroautophagy, the main route of cellular degradation, is initiated from an isolated membrane (phagophore) forming the double membraned autophagosome to sequester cytosolic material. Subsequent fusion of autophagosomes with lysosomes forms the autolysosome for hydrolase-mediated degradation of its contents. In chaperone-mediated autophagy, the cytosolic chaperone protein HSC70 targets and translocates unfolded proteins directly to lysosomes through binding to the lysosomal receptor LAMP2A. Compared to non-selective/bulk macroautophagy, selective mitophagy labels only damaged mitochondria for downstream autophagic degradation. See text for more detailed description of PD gene-mediated effects on various types and steps of the autophagic-lysosomal pathway.

Figure 2.. The multidirectional forward loop of PD-related genes, autophagy function, and PD pathology.

A variety of PD-related genes and encoded proteins are functionally linked to the autophagy pathway. Disease-associated mutations strongly impair the initiation and flux of this essential degradation process. In turn, autophagy defects dysregulate gene transcription and translation of encoded proteins as well as their downstream signaling pathways or enzymatic activities. In addition, autophagy deficiency or blockage of autophagic flux increases oligomerization or aggregation of α-synuclein and tau proteins in the PD brain. This will exacerbate levels of autophagy dysfunction and results in a pathological feedforward loop that will also interfere with physiological functions of other essential proteins.