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Brain Advance Access published online on January 10, 2008
Brain, doi:10.1093/brain/awm318
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Review Article

The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease

Tianhong Pan1, Seiji Kondo2, Weidong Le1 and Joseph Jankovic3

1Parkinson's Disease Research Laboratory, Baylor College of Medicine, 2Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center and 3Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA

Correspondence to: Correspondence to: Joseph Jankovic, MD, Professor of Neurology, Director, Parkinson's Disease Center, and Movement Disorders Clinic, Baylor College of Medicine, Department of Neurology, 6550 Fannin #1801Houston, TX 77030, USA. E-mail: josephj{at}bcm.tmc.edu

The ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are the two most important mechanisms that normally repair or remove abnormal proteins. Alterations in the function of these systems to degrade misfolded and aggregated proteins are being increasingly recognized as playing a pivotal role in the pathogenesis of many neurodegenerative disorders such as Parkinson's disease. Dysfunction of the UPS has been already strongly implicated in the pathogenesis of this disease and, more recently, growing interest has been shown in identifying the role of ALP in neurodegeneration. Mutations of {alpha}-synuclein and the increase of intracellular concentrations of non-mutant {alpha}-synuclein have been associated with Parkinson's disease phenotype. The demonstration that {alpha}-synuclein is degraded by both proteasome and autophagy indicates a possible linkage between the dysfunction of the UPS or ALP and the occurrence of this disorder. The fact that mutant {alpha}-synucleins inhibit ALP functioning by tightly binding to the receptor on the lysosomal membrane for autophagy pathway further supports the assumption that impairment of the ALP may be related to the development of Parkinson's disease. In this review, we summarize the recent findings related to this topic and discuss the unique role of the ALP in this neurogenerative disorder and the putative therapeutic potential through ALP enhancement.

Key Words: autophagy-lysosome pathway; neurodegenerative disease; neuroprotection; Parkinson's disease; ubiquitin-proteasome system

Abbreviations: ALP, autophagy-lysosome pathway; Ambra1, activating molecule in beclin1-regulated autophagy; BafA1, bafilomycin A1; CMA, chaperone-mediated autophagy; HDAC6, histone deacetylase 6; IMPase, inositol monophosphatase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homologue; 3-MA, 3-methyladenine; UPS, ubiquitin-proteasome system

Received July 24, 2007. Revised October 19, 2007. Accepted December 11, 2007.


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