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. 2013 Jul;136(Pt 7):2130-46.
doi: 10.1093/brain/awt131. Epub 2013 Jun 11.

Boosting chaperone-mediated autophagy in vivo mitigates α-synuclein-induced neurodegeneration

Maria Xilouri  1 , Oeystein Roed Brekk, Natalie Landeck, Pothitos M Pitychoutis, Themistoklis Papasilekas, Zoi Papadopoulou-Daifoti, Deniz Kirik, Leonidas Stefanis
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Boosting chaperone-mediated autophagy in vivo mitigates α-synuclein-induced neurodegeneration

Maria Xilouri et al. Brain. 2013 Jul.

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.

Keywords: Lamp2a; Parkinson’s disease; alpha-synuclein; chaperone-mediated autophagy; neurotoxicity.

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