L‐DOPA regulates α‐synuclein accumulation in experimental parkinsonism
Neuropathol Appl Neurobiol. 2020-12-04; :
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Deffains M(1), Canron MH(1), Teil M(1), Li Q(2)(3), Dehay B(1), Bezard E(1)(2)(3), Fernagut PO(1)(4).
(1)Univ. Bordeaux, CNRS, UMR 5293, IMN, F-33000, Bordeaux, France.
(2)Motac Neuroscience, Manchester, M15 6WE, United Kingdom.
(3)Institute of Laboratory Animal Sciences, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
(4)Université de Poitiers, INSERM U-1084, Laboratoire de Neurosciences Expérimentales et Cliniques, UMR_S 1084, F-86000, Poitiers, France.
AIMS: 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 of PD and determined the effect of chronic L-DOPA treatment on MPTP-induced α-synuclein pathology.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.