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TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.

Decressac, Mickael LU ; Mattsson, Bengt LU ; Weikop, Pia; Lundblad, Martin LU ; Jakobsson, Johan LU and Björklund, Anders LU (2013) In Proceedings of the National Academy of Sciences 110(19). p.1817-1826
Abstract
The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by... (More)
The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of α-synuclein oligomers, and were aggravated by microRNA-128-mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synuclein-induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
110
issue
19
pages
1817 - 1826
publisher
National Acad Sciences
external identifiers
  • wos:000319327700015
  • pmid:23610405
  • scopus:84877351078
ISSN
1091-6490
DOI
10.1073/pnas.1305623110
language
English
LU publication?
yes
id
78bfa4db-5b5f-4b2a-872b-4fdcd3521b43 (old id 3733456)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23610405?dopt=Abstract
date added to LUP
2013-05-04 20:21:28
date last changed
2019-04-23 01:11:28
@article{78bfa4db-5b5f-4b2a-872b-4fdcd3521b43,
  abstract     = {The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of α-synuclein oligomers, and were aggravated by microRNA-128-mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synuclein-induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.},
  author       = {Decressac, Mickael and Mattsson, Bengt and Weikop, Pia and Lundblad, Martin and Jakobsson, Johan and Björklund, Anders},
  issn         = {1091-6490},
  language     = {eng},
  number       = {19},
  pages        = {1817--1826},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.},
  url          = {http://dx.doi.org/10.1073/pnas.1305623110},
  volume       = {110},
  year         = {2013},
}