L-DOPA regulates α-synuclein accumulation in experimental parkinsonism.
MPTP
Parkinson's disease
levodopa
macaque
protein aggregation
tau
α-synuclein
Journal
Neuropathology and applied neurobiology
ISSN: 1365-2990
Titre abrégé: Neuropathol Appl Neurobiol
Pays: England
ID NLM: 7609829
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
09
10
2020
received:
30
04
2020
accepted:
28
11
2020
pubmed:
5
12
2020
medline:
23
2
2022
entrez:
4
12
2020
Statut:
ppublish
Résumé
Widespread accumulation of misfolded α-synuclein aggregates is a key feature of Parkinson's disease (PD). Although the pattern and extent of α-synuclein accumulation through PD brains is known, the impact of chronic dopamine-replacement therapy (the gold-standard pharmacological treatment of PD) on the fate of α-synuclein is still unknown. Here, we investigated the distribution and accumulation of α-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) non-human primate model of PD and determined the effect of chronic L-DOPA treatment on MPTP-induced α-synuclein pathology. We measured the density of α-synuclein and tau immuno-positive neurons in the substantia nigra, putamen, hippocampal CA1 region, temporal cortex and dentate nucleus of control, MPTP and MPTP+L-DOPA-treated monkeys. Moreover, we also extracted and quantified Triton-X (TX) soluble and insoluble α-synuclein in putamen and hippocampus samples from a separate cohort of control, MPTP and MPTP+L-DOPA-treated monkeys. MPTP-induced α-synuclein accumulation in NHP model of PD was not limited to the substantia nigra but also occurred in the putamen, hippocampal CA1 region and temporal cortex. Tau was increased only in the temporal cortex. Moreover, increased intraneuronal TX insoluble α-synuclein was truncated, but not in the structural form of Lewy bodies. The MPTP-induced increase in α-synuclein levels was abolished in animals having received L-DOPA in all the brain regions, except in the substantia nigra. Dopamine replacement therapy can dramatically ameliorate α-synuclein pathology in the MPTP NHP model of PD. Therefore, patient's dopaminergic medication should be systematically considered when assessing α-synuclein as a biomarker for diagnosis, monitoring disease progression and response to disease-modifying treatments.
Substances chimiques
Dopamine Agents
0
alpha-Synuclein
0
Levodopa
46627O600J
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
9P21XSP91P
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
532-543Informations de copyright
© 2020 British Neuropathological Society.
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