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

• alpha-Synuclein levels are critical to Parkinson's disease pathogenesis. Wild-type alpha-synuclein is degraded partly by chaperone-mediated autophagy, and aberrant alpha-synuclein may act as an inhibitor of the pathway. To address whether the induction of chaperone-mediated autophagy may represent a potential therapy against alpha-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 alpha-synuclein turnover, and selective protection against adenoviral-mediated wild-type alpha-synuclein neurotoxicity. Protection was observed even when the steady-state levels of alpha-synuclein were unchanged, suggesting that it occurred through the attenuation of alpha-synuclein-mediated dysfunction of chaperone-mediated autophagy. Overexpression of the lysosomal receptor through the nigral injection of recombinant adeno-associated virus vectors effectively ameliorated alpha-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 alpha-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 alpha-synuclein levels.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

alpha-synuclein

chaperone-mediated autophagy

Lamp2a

neurotoxicity

Parkinson's disease

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