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

Xilouri, Maria; Brekk, Oeystein Roed; Landeck, Natalie LU ; Pitychoutis, Pothitos M.; Papasilekas, Themistoklis; Papadopoulou-Daifoti, Zoi; Kirik, Deniz LU and Stefanis, Leonidas (2013) In Brain 136. p.2130-2146
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alpha-synuclein, chaperone-mediated autophagy, Lamp2a, neurotoxicity, Parkinson's disease
in
Brain
volume
136
pages
2130 - 2146
publisher
Oxford University Press
external identifiers
  • wos:000321060200020
  • scopus:84879962810
ISSN
1460-2156
DOI
10.1093/brain/awt131
language
English
LU publication?
yes
id
48c7b2bf-da51-479b-8878-7a6e62e0ed90 (old id 3979602)
date added to LUP
2013-09-02 07:30:16
date last changed
2019-02-17 03:16:39
@article{48c7b2bf-da51-479b-8878-7a6e62e0ed90,
  abstract     = {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.},
  author       = {Xilouri, Maria and Brekk, Oeystein Roed and Landeck, Natalie and Pitychoutis, Pothitos M. and Papasilekas, Themistoklis and Papadopoulou-Daifoti, Zoi and Kirik, Deniz and Stefanis, Leonidas},
  issn         = {1460-2156},
  keyword      = {alpha-synuclein,chaperone-mediated autophagy,Lamp2a,neurotoxicity,Parkinson's disease},
  language     = {eng},
  pages        = {2130--2146},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {Boosting chaperone-mediated autophagy in vivo mitigates alpha-synuclein-induced neurodegeneration},
  url          = {http://dx.doi.org/10.1093/brain/awt131},
  volume       = {136},
  year         = {2013},
}