title: Boosting chaperone-mediated autophagy in vivo mitigates α-synuclein-induced neurodegeneration.
abstract: α-Synuclein levels are critical to Parkinson's disease pathogenesis. Wild-type α-synuclein is degraded partly by chaperone-mediated autophagy, and aberrant α-synuclein may act as an inhibitor of the pathway. To address whether the induction of chaperone-mediated autophagy may represent a potential therapy against α-synuclein-induced neurotoxicity, we overexpressed lysosomal-associated membrane protein 2a, the rate-limiting step of chaperone-mediated autophagy, in human neuroblastoma SH-SY5Y cells, rat primary cortical neurons in vitro, and nigral dopaminergic neurons in vivo. Overexpression of the lysosomal-associated membrane protein 2a in cellular systems led to upregulation of chaperone-mediated autophagy, decreased α-synuclein turnover, and selective protection against adenoviral-mediated wild-type α-synuclein neurotoxicity. Protection was observed even when the steady-state levels of α-synuclein were unchanged, suggesting that it occurred through the attenuation of α-synuclein-mediated dysfunction of chaperone-mediated autophagy. Overexpression of the lysosomal receptor through the nigral injection of recombinant adeno-associated virus vectors effectively ameliorated α-synuclein-induced dopaminergic neurodegeneration by increasing the survival of neurons located in the substantia nigra as well as the axon terminals located in the striatum, which was associated with a reduction in total α-synuclein levels and related aberrant species. We conclude that induction of chaperone-mediated autophagy may provide a novel therapeutic strategy in Parkinson's disease and related synucleinopathies through two different mechanisms: amelioration of dysfunction of chaperone-mediated autophagy and lowering of α-synuclein levels.
authors.affiliation: Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. mxilouri@bioacademy.gr
authors.forename: Maria
authors.initials: M
authors.lastname: Xilouri
authors.forename: Oeystein Roed
authors.initials: OR
authors.lastname: Brekk
authors.forename: Natalie
authors.initials: N
authors.lastname: Landeck
authors.forename: Pothitos M
authors.initials: PM
authors.lastname: Pitychoutis
authors.forename: Themistoklis
authors.initials: T
authors.lastname: Papasilekas
authors.forename: Zoi
authors.initials: Z
authors.lastname: Papadopoulou-Daifoti
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stefanis
mesh_terms: D000661:Amphetamine; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000276:immunology; D006388:Hemagglutinins / Q000378:metabolism; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D051381:Rats; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D006388:Hemagglutinins; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D018942:Macrolides; D018832:Molecular Chaperones; D051844:alpha-Synuclein; C057620:bafilomycin A; D049452:Green Fluorescent Proteins; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine
keywords: Lamp2a; Parkinson’s disease; alpha-synuclein; chaperone-mediated autophagy; neurotoxicity