Institut des Sciences Cognitives Marc Jeannerod (ISCMJ), Unité Mixte de Recherche 5229 du Centre National de la Recherche Scientifique (CNRS), 69675 Bron, France.
UFR Biosciences, Université Claude Bernard, Lyon 1, 69100 Villeurbanne, France.
Int J Mol Sci. 2022 Aug 2;23(15):8586. doi: 10.3390/ijms23158586.
Parkinson's disease (PD) is characterized by cell loss in the substantia nigra and the presence of alpha-synuclein (α-syn)-containing neuronal Lewy bodies. While α-syn has received major interest in the pathogenesis of PD, the function of beta- and gamma-synucleins (β-syn and γ-syn, respectively) is not really known. Yet, these proteins are members of the same family and also concentrated in neuronal terminals. The current preclinical study investigated the expression levels of α-, β-, and γ-synucleins in brainstem regions involved in PD physiopathology. We analyzed synuclein expression in the substantia nigra, raphe nuclei, pedunculopontine nucleus, and locus coeruleus from control and parkinsonian (by MPTP) macaques. MPTP-intoxicated monkeys developed a more or less severe parkinsonian score and were sacrificed after a variable post-MPTP period ranging from 1 to 20 months. The expression of the three synucleins was increased in the substantia nigra after MPTP, and this increase correlates positively, although not very strongly, with cell loss and motor score and not with the time elapsed after intoxication. In the dorsal raphe nucleus, the expression of the three synucleins was also increased, but only α- and γ-Syn are linked to the motor score and associated cell loss. Finally, although no change in synuclein expression was demonstrated in the locus coeruleus after MPTP, we found increased expression levels of γ-Syn, which are only correlated with cell loss in the pedunculopontine nucleus. Altogether, our data suggest that these proteins may play a key role in brainstem regions and mesencephalic tegmentum. Given the involvement of these brain regions in non-motor symptoms of PD, these data also strengthen the relevance of the MPTP macaque model of PD, which exhibits pathological changes beyond nigral DA cell loss and α-synucleinopathy.
帕金森病（PD）的特征是黑质细胞丢失和存在含有α-突触核蛋白（α-syn）的神经元Lewy 体。虽然α-syn 在 PD 的发病机制中受到了极大的关注，但β-和γ-突触核蛋白（β-syn 和 γ-syn，分别）的功能却并不为人所知。然而，这些蛋白质是同一个家族的成员，也集中在神经元末梢。目前的临床前研究调查了参与 PD 病理生理学的脑干区域中α-、β-和γ-突触核蛋白的表达水平。我们分析了对照组和帕金森病（MPTP 诱导）猕猴的黑质、中缝核、脑桥被盖核和蓝斑中突触核蛋白的表达。MPTP 中毒的猴子表现出或多或少严重的帕金森病评分，并在 MPTP 后 1 至 20 个月不等的可变时间后被处死。MPTP 后黑质中三种突触核蛋白的表达增加，这种增加与细胞丢失和运动评分呈正相关，虽然不是很强，与中毒后经过的时间无关。在中缝背核中，三种突触核蛋白的表达也增加了，但只有α-和γ-Syn 与运动评分和相关的细胞丢失有关。最后，尽管在 MPTP 后蓝斑中没有观察到突触核蛋白表达的变化，但我们发现了γ-Syn 表达水平的增加，这仅与脑桥被盖核中的细胞丢失相关。总之，我们的数据表明这些蛋白质可能在脑干区域和中脑被盖区发挥关键作用。鉴于这些脑区参与 PD 的非运动症状，这些数据也加强了 MPTP 猕猴 PD 模型的相关性，该模型表现出除黑质 DA 细胞丢失和α-synucleinopathy 之外的病理性改变。
