title: Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats.
abstract: Chaperone-mediated autophagy (CMA) involves the selective lysosomal degradation of cytosolic proteins such as SNCA (synuclein α), a protein strongly implicated in Parkinson disease (PD) pathogenesis. However, the physiological role of CMA and the consequences of CMA failure in the living brain remain elusive. Here we show that CMA inhibition in the adult rat substantia nigra via adeno-associated virus-mediated delivery of short hairpin RNAs targeting the LAMP2A receptor, involved in CMA's rate limiting step, was accompanied by intracellular accumulation of SNCA-positive puncta, which were also positive for UBIQUITIN, and in accumulation of autophagic vacuoles within LAMP2A-deficient nigral neurons. Strikingly, LAMP2A downregulation resulted in progressive loss of nigral dopaminergic neurons, severe reduction in striatal dopamine levels/terminals, increased astro- and microgliosis and relevant motor deficits. Thus, this study highlights for the first time the importance of the CMA pathway in the dopaminergic system and suggests that CMA impairment may underlie PD pathogenesis.
authors.affiliation: a Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens , Athens , Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Xilouri
authors.affiliation: a Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens , Athens , Greece.|b University of Crete, School of Medicine , Heraklion , Crete , Greece.
authors.forename: Oeystein Roed
authors.initials: OR
authors.lastname: Brekk
authors.affiliation: a Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens , Athens , Greece.
authors.forename: Alexia
authors.initials: A
authors.lastname: Polissidis
authors.affiliation: c Research Unit of Histochemistry and Electron Microscopy , 1st Department of Psychiatry, University of Athens Medical School, Eginition Hospital , Athens , Greece.
authors.forename: Margarita
authors.initials: M
authors.lastname: Chrysanthou-Piterou
authors.affiliation: d Center of Basic Research, Biomedical Research Foundation of the Academy of Athens , Athens , Greece.|e Neurobiology Research Institute, Theodor Theohari Cozzika Foundation , Athens , Greece.
authors.forename: Ismini
authors.initials: I
authors.lastname: Kloukina
authors.affiliation: a Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens , Athens , Greece.|f Second Department of Neurology , National and Kapodistrian University of Athens Medical School , Athens , Greece.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stefanis
mesh_terms: D000818:Animals; D001343:Autophagy; D001522:Behavior, Animal; D000229:Dependovirus / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000473:pathology* / Q000648:ultrastructure; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D005822:Genetic Vectors / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D017208:Rats, Wistar; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic; D025801:Ubiquitin / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat; D025801:Ubiquitin; D051844:alpha-Synuclein
keywords: LAMP2A; Parkinson disease; chaperone-mediated autophagy; lysosomes; synuclein α