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L‐DOPA regulates α‐synuclein accumulation in experimental parkinsonism
Neuropathology and Applied Neurobiology ( IF 4.0 ) Pub Date : 2020-12-16 , DOI: 10.1111/nan.12678 Marc Deffains 1 , Marie-Hélène Canron 1 , Margaux Teil 1 , Qin Li 2, 3 , Benjamin Dehay 1 , Erwan Bezard 1, 2, 3 , Pierre-Olivier Fernagut 1, 4
Neuropathology and Applied Neurobiology ( IF 4.0 ) Pub Date : 2020-12-16 , DOI: 10.1111/nan.12678 Marc Deffains 1 , Marie-Hélène Canron 1 , Margaux Teil 1 , Qin Li 2, 3 , Benjamin Dehay 1 , Erwan Bezard 1, 2, 3 , Pierre-Olivier Fernagut 1, 4
Affiliation
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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.
中文翻译：
L-DOPA 调节实验性帕金森症中 α-突触核蛋白的积累
目的 错误折叠的 α-突触核蛋白聚集体的广泛积累是帕金森病 (PD) 的一个关键特征。尽管已知 PD 大脑中 α-突触核蛋白积累的模式和程度，但慢性多巴胺替代疗法（PD 的金标准药物治疗）对 α-突触核蛋白命运的影响仍然未知。在这里，我们研究了 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 非人灵长类 PD 中 α-突触核蛋白的分布和积累，并确定了慢性 L-DOPA 治疗的效果MPTP诱导的α-突触核蛋白病理学。方法 我们测量了对照组、MPTP 和 MPTP+L-DOPA 处理的猴子黑质、壳核、海马 CA1 区、颞叶皮层和齿状核中 α-突触核蛋白和 tau 免疫阳性神经元的密度。而且，我们还从一组单独的对照组、MPTP 和 MPTP+L-DOPA 处理的猴子中提取和量化了壳核和海马样品中的 Triton-X (TX) 可溶性和不溶性 α-突触核蛋白。结果MPTP诱导的PD NHP模型中α-突触核蛋白的积累不仅限于黑质，还发生在壳核、海马CA1区和颞叶皮层。Tau 仅在颞叶皮层增加。此外，增加的神经元内 TX 不溶性 α-突触核蛋白被截断，但不是路易体的结构形式。MPTP 诱导的 α-突触核蛋白水平增加在除黑质外的所有大脑区域接受 L-DOPA 的动物中被消除。结论 多巴胺替代疗法可以显着改善 PD 的 MPTP NHP 模型中的 α-突触核蛋白病理学。因此，耐心'
更新日期：2020-12-16
中文翻译：
L-DOPA 调节实验性帕金森症中 α-突触核蛋白的积累
目的 错误折叠的 α-突触核蛋白聚集体的广泛积累是帕金森病 (PD) 的一个关键特征。尽管已知 PD 大脑中 α-突触核蛋白积累的模式和程度，但慢性多巴胺替代疗法（PD 的金标准药物治疗）对 α-突触核蛋白命运的影响仍然未知。在这里，我们研究了 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 非人灵长类 PD 中 α-突触核蛋白的分布和积累，并确定了慢性 L-DOPA 治疗的效果MPTP诱导的α-突触核蛋白病理学。方法 我们测量了对照组、MPTP 和 MPTP+L-DOPA 处理的猴子黑质、壳核、海马 CA1 区、颞叶皮层和齿状核中 α-突触核蛋白和 tau 免疫阳性神经元的密度。而且，我们还从一组单独的对照组、MPTP 和 MPTP+L-DOPA 处理的猴子中提取和量化了壳核和海马样品中的 Triton-X (TX) 可溶性和不溶性 α-突触核蛋白。结果MPTP诱导的PD NHP模型中α-突触核蛋白的积累不仅限于黑质，还发生在壳核、海马CA1区和颞叶皮层。Tau 仅在颞叶皮层增加。此外，增加的神经元内 TX 不溶性 α-突触核蛋白被截断，但不是路易体的结构形式。MPTP 诱导的 α-突触核蛋白水平增加在除黑质外的所有大脑区域接受 L-DOPA 的动物中被消除。结论 多巴胺替代疗法可以显着改善 PD 的 MPTP NHP 模型中的 α-突触核蛋白病理学。因此，耐心'
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