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      Autophagy and Alpha-Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies.

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          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.

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          Author and article information

          Journal
          Mov. Disord.
          Movement disorders : official journal of the Movement Disorder Society
          1531-8257
          0885-3185
          Feb 2016
          : 31
          : 2
          Affiliations
          [1 ] Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
          [2 ] Second Department of Neurology, University of Athens Medical School, Athens, Greece.
          Article
          10.1002/mds.26477
          26813776
          6148b3f7-9fc6-4c91-ba4c-7452e295b6fb
          © 2016 International Parkinson and Movement Disorder Society.
          History

          Parkinson's disease,alpha-synuclein,chaperone-mediated autophagy,glucocerebrosidase,lysosomes,macroautophagy,neurodegeneration,synucleinopathies

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