Boosting chaperone-mediated autophagy in vivo mitigates alpha-synuclein-induced neurodegeneration
Författare
Summary, in English
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.
Avdelning/ar
Publiceringsår
2013
Språk
Engelska
Sidor
2130-2146
Publikation/Tidskrift/Serie
Brain
Volym
136
Dokumenttyp
Artikel i tidskrift
Förlag
Oxford University Press
Ämne
- Neurology
Nyckelord
- alpha-synuclein
- chaperone-mediated autophagy
- Lamp2a
- neurotoxicity
- Parkinson's disease
Status
Published
Forskningsgrupp
- Brain Repair and Imaging in Neural Systems (BRAINS)
ISBN/ISSN/Övrigt
- ISSN: 1460-2156