title: Autophagy and Alpha-Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies.
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.
authors.affiliation: Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Xilouri
authors.affiliation: Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Oeystein Roed
authors.initials: OR
authors.lastname: Brekk
authors.affiliation: Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.|Second Department of Neurology, University of Athens Medical School, Athens, Greece.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stefanis
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D005962:Glucosylceramidase
keywords: Parkinson's disease; alpha-synuclein; chaperone-mediated autophagy; glucocerebrosidase; lysosomes; macroautophagy; neurodegeneration; synucleinopathies