REST Protects Dopaminergic Neurons from Mitochondrial and α-Synuclein Oligomer Pathology in an Alpha Synuclein Overexpressing BAC-Transgenic Mouse Model.
Animals
CRISPR-Cas Systems
Chromosomes, Artificial, Bacterial
Dopaminergic Neurons
/ pathology
Female
GABAergic Neurons
/ pathology
Gene Expression Regulation
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria
/ pathology
Oxidative Stress
Parkinson Disease
/ pathology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ genetics
Repressor Proteins
/ genetics
Synucleinopathies
/ genetics
alpha-Synuclein
/ genetics
Parkinson's
REST
alpha-synuclein
neurodegeneration
neuroprotection
oligomers
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN: 1529-2401
Titre abrégé: J Neurosci
Pays: United States
ID NLM: 8102140
Informations de publication
Date de publication:
21 04 2021
21 04 2021
Historique:
received:
11
06
2020
revised:
03
01
2021
accepted:
05
01
2021
pubmed:
11
2
2021
medline:
20
11
2021
entrez:
10
2
2021
Statut:
ppublish
Résumé
Alpha-synuclein pathology is associated with dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's patients. Working across human and mouse models, we investigated mechanisms by which the accumulation of soluble α-synuclein oligomers leads to neurodegeneration. Biochemical analysis of the midbrain of α-synuclein overexpressing BAC-transgenic male and female mice revealed age- and region-dependent mitochondrial dysfunction and accumulation of damaged proteins downstream of the RE1 Silencing Transcription Factor (REST). Vulnerable SN dopaminergic neurons displayed low REST levels compared with neighboring protected SN GABAergic neurons, which correlated with the accumulation of α-synuclein oligomers and disrupted mitochondrial morphology. Consistent with a protective role, REST levels were reduced in patient induced pluripotent stem cell-derived dopaminergic neurons carrying the
Identifiants
pubmed: 33563726
pii: JNEUROSCI.1478-20.2021
doi: 10.1523/JNEUROSCI.1478-20.2021
pmc: PMC8055072
doi:
Substances chimiques
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
Ppargc1a protein, mouse
0
RE1-silencing transcription factor
0
Repressor Proteins
0
alpha-Synuclein
0
Banques de données
PDB
['4WNC']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3731-3746Subventions
Organisme : Medical Research Council
ID : MR/N029453/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P007058/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/1
Pays : United Kingdom
Organisme : Parkinson's UK
ID : J-0901
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_MR/N50192X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M024962/1
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021 the authors.
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