Expert Reviews in Molecular Medicine

Review Article

Autophagic pathways in Parkinson disease and related disorders

Maria Xilouria1 and Leonidas Stefanisa1a2 c1

a1 Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

a2 Second Department of Neurology, University of Athens Medical School, Athens, Greece

Abstract

Macroautophagy and chaperone-mediated autophagy (CMA) are the two main mammalian lysosomal proteolytic systems. In macroautophagy, double-membrane structures engulf organelles and other intracellular constituents through a highly regulated process that involves the formation of autophagic vacuoles and their fusion with lysosomes. In CMA, selected proteins are targeted through a nonvesicular pathway to a transport complex at the lysosomal membrane, through which they are threaded into the lysosomes and degraded. Autophagy is important in development, differentiation, cellular remodelling and survival during nutrient starvation. Increasing evidence suggests that autophagic dysregulation causes accumulation of abnormal proteins or damaged organelles, which is a characteristic of chronic neurodegenerative conditions, such as Parkinson disease (PD). Evidence from post-mortem material, transgenic mice, and animal and cellular models of PD suggests that both major autophagic pathways are malfunctioning. Numerous connections exist between proteins genetically linked to autosomal dominant PD, in particular α-synuclein and LRRK2, and autophagic pathways. However, proteins involved in recessive PD, such as PINK1 and Parkin (PINK2), function in the process of mitophagy, whereby damaged mitochondria are selectively engulfed by macroautophagy. This wealth of new data suggests that both autophagic pathways are potential targets for therapeutic intervention in PD and other related neurodegenerative conditions.

(Online publication March 21 2011)

Correspondence

c1 Corresponding author: Leonidas Stefanis, Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens (BRFAA) 4, Soranou Efesiou Street, Athens 11527, Greece. E-mail: lstefanis@bioacademy.gr