Autophagy and Alpha‐Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies. Issue 2 (27th January 2016)

• Record Type: Journal Article
• Authors: Xilouri, Maria; Brekk, Oeystein Roed; Stefanis, Leonidas
• Is Part Of: Movement disorders. Volume 31:Issue 2(2016)
• Page Start: 178
• Page End: 192
• Publication Date: 2016-01-27
• Subjects: alpha‐synuclein -- chaperone‐mediated autophagy -- glucocerebrosidase -- lysosomes -- macroautophagy -- neurodegeneration -- Parkinson's disease -- synucleinopathies; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.26477
• Languages: English
• ISSNs: 0885-3185

Abstract

ABSTRACT: Evidence from human postmortem material, transgenic mice, and cellular/animal models of PD link alpha‐synuclein accumulation to alterations in the autophagy lysosomal pathway. Conversely, alpha‐synuclein mutations related to PD pathogenesis, as well as post‐translational modifications of the wild‐type protein, result in the generation of aberrant species that may impair further the function of the autophagy lysosomal pathway, thus generating a vicious cycle leading to neuronal death. Moreover, PD‐linked mutations in lysosomal‐related genes, such as glucocerebrosidase, have been also shown to contribute to alpha‐synuclein accumulation and related toxicity, indicating that lysosomal dysfunction may, in part, account for the neurodegeneration observed in synucleinopathies. In the current review, we summarize findings related to the inter‐relationship between alpha‐synuclein and lysosomal proteolytic pathways, focusing especially on recent experimental strategies based on the manipulation of the autophagy lysosomal pathway to counteract alpha‐synuclein‐mediated neurotoxicity in vivo. Pinpointing the factors that regulate alpha‐synuclein association to the lysosome may represent potential targets for therapeutic interventions in PD and related synucleinopathies. © 2016 International Parkinson and Movement Disorder Society