Boosting chaperone-mediated autophagy in vivo mitigates alpha-synuclein-induced neurodegeneration
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3979602
- author
- Xilouri, Maria ; Brekk, Oeystein Roed ; Landeck, Natalie LU ; Pitychoutis, Pothitos M. ; Papasilekas, Themistoklis ; Papadopoulou-Daifoti, Zoi ; Kirik, Deniz LU and Stefanis, Leonidas
- organization
- publishing date
- 2013
- 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
- pmid:23757764
- 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
- 2016-04-01 10:37:06
- date last changed
- 2022-05-13 18:24:52
@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}},
keywords = {{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}},
doi = {{10.1093/brain/awt131}},
volume = {{136}},
year = {{2013}},
}