The role of autophagy in Parkinson's disease

Abstract

Great progress has been made toward understanding the pathogenesis of Parkinson's disease (PD) during the past two decades, mainly as a consequence of the discovery of specific gene mutations contributing to the onset of PD. Recently, dysregulation of the autophagy pathway has been observed in the brains of PD patients and in animal models of PD, indicating the emerging role of autophagy in this disease. Indeed, autophagy is increasingly implicated in a number of pathophysiologies, including various neurodegenerative diseases. This article will lead you through the connection between autophagy and PD by introducing the concept and physiological function of autophagy, and the proteins related to autosomal dominant and autosomal recessive PD, particularly α-synuclein and PINK1-PARKIN, as they pertain to autophagy.

Figure 1.

Schematic model of the three main types of autophagy. The modes of autophagy differ depending on the nature of the substrate and the site of sequestration. In chaperone-mediated autophagy, the substrates contain a KFERQ-consensus motif, are unfolded by HSC70 chaperones, and translocate directly across the lysosome membrane via interaction with a LAMP-2A oligomer. There are various types of microautophagy-like processes including micropexophagy and micromitophagy, the selective degradation of peroxisomes and mitochondria, respectively. Again, sequestration occurs at the lysosome-limiting membrane, but the substrates do not have to be unfolded. Macroautophagy uses a double-membrane phagophore to sequester the cargo. Essentially any cytoplasmic component can be enwrapped by a phagophore, which expands into an autophagosome. Fusion with the lysosome allows the cargo to be degraded, and the resulting macromolecules are released into the cytosol through permeases, allowing them to be reused for anabolic processes.