Structurally distinct α-synuclein fibrils induce robust parkinsonian pathology.
Lewy body
Parkinson's disease
alpha-synuclein
animal model
propagation
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
16
05
2019
revised:
24
07
2019
accepted:
26
08
2019
pubmed:
24
10
2019
medline:
16
1
2021
entrez:
24
10
2019
Statut:
ppublish
Résumé
Alpha-synuclein (α-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with α-syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for α-syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of α-syn G51D mutation using a murine model generated by G51D α-syn fibril injection into the brain. Structural analysis of wild-type and G51D α-syn-fibrils were performed using Fourier transform infrared spectroscopy. The ability of α-syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of α-syn fibrils was then used to evaluate the propagation pattern of α-syn and related cellular changes. We found that G51D α-syn fibrils have higher β-sheet contents than wild-type α-syn fibrils. The addition of G51D α-syn fibrils to mammalian cells overexpressing α-syn resulted in the formation of phosphorylated α-syn inclusions at a higher rate. Similarly, an injection of G51D α-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated α-syn pathology. Notably, the mice injected with G51D α-syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment. Our findings indicate that the structural difference of G51D α-syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation-linked Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
Identifiants
pubmed: 31643109
doi: 10.1002/mds.27887
pmc: PMC7202333
mid: NIHMS1582855
doi:
Substances chimiques
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
256-267Subventions
Organisme : NIH HHS
ID : P51 OD011132
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS045962
Pays : United States
Organisme : NCRR NIH HHS
ID : P51 RR000165
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS045962
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS073994
Pays : United States
Informations de copyright
© 2019 International Parkinson and Movement Disorder Society.
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