Costa Giulia, Pinna Annalisa, Porceddu Pier Francesca, Casu Maria Antonietta, Di Maio Anna, Napolitano Francesco, Usiello Alessandro, Morelli Micaela
Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
National Research Council of Italy, Neuroscience Institute, Cagliari, Italy.
Front Aging Neurosci. 2018 May 31;10:163. doi: 10.3389/fnagi.2018.00163. eCollection 2018.
We have recently shown that male Rhes knockout (KO) mice develop a mild form of spontaneous Parkinson's disease (PD)-like phenotype, characterized by motor impairment and a decrease in nigrostriatal dopamine (DA) neurons. Experimental evidence has implicated neuroinflammation in PD progression, and the presence of activated glial cells has been correlated with DA neuron degeneration. Despite this, several factors, such as gender, have been found to affect DAergic neuron degeneration and influence neuroinflammation, explaining the differences between men and women in the etiology of PD. On these basis, we studied age and gender differences in DA neuron degeneration and gliosis in the nigrostriatal system of adult (3-month-old) and middle aged (12-month-old) male and female Rhes wild-type (WT) and KO mice. Through immunohistochemistry, tyrosine hydroxylase (TH), microglial (complement type 3 receptor [CD11b]) and astroglial (glial fibrillary acid protein [GFAP]) increase, were evaluated. Adult male Rhes KO mice showed a decrease in TH and an increase in CD11b, both in the caudate putamen (CPu) and substantia nigra pars compacta (SNc), and an increase in GFAP in the CPu. In contrast, adult female Rhes KO mice showed only a decrease in TH in the SNc, whereas no modifications to the levels of GFAP and CD11b were observed in the CPu or SNc. Middle aged male Rhes KO mice showed a decrease in TH in the CPu and SNc, and an increase in GFAP and CD11b in the SNc. Middle aged female Rhes KO mice showed a decrease in TH in the CPu and SNc and an increase in CD11b only in the CPu, but no modifications to GFAP levels. The more marked DA neuron degeneration and neuroinflammation in male compared with female Rhes KO mice, while confirming the role of Rhes as an important protein for DA neuron survival, gives support to Rhes KO mice as a valuable preclinical model for studying the vulnerability factors of DA neuron degeneration as in PD.
我们最近发现，雄性Rhes基因敲除（KO）小鼠会出现一种轻度的自发性帕金森病（PD）样表型，其特征为运动功能受损以及黑质纹状体多巴胺（DA）神经元减少。实验证据表明神经炎症与PD的进展有关，并且活化的神经胶质细胞的存在与DA神经元变性相关。尽管如此，人们发现诸如性别等多种因素会影响DA能神经元变性并影响神经炎症，这解释了男性和女性在PD病因方面的差异。在此基础上，我们研究了成年（3个月大）和中年（12个月大）雄性和雌性Rhes野生型（WT）和KO小鼠黑质纹状体系统中DA神经元变性和胶质增生的年龄和性别差异。通过免疫组织化学，评估了酪氨酸羟化酶（TH）、小胶质细胞（补体3型受体[CD11b]）和星形胶质细胞（胶质纤维酸性蛋白[GFAP]）的增加情况。成年雄性Rhes KO小鼠在尾壳核（CPu）和黑质致密部（SNc）中均表现出TH减少以及CD11b增加，并且在CPu中GFAP增加。相比之下，成年雌性Rhes KO小鼠仅在SNc中表现出TH减少，而在CPu或SNc中未观察到GFAP和CD11b水平的改变。中年雄性Rhes KO小鼠在CPu和SNc中表现出TH减少，并且在SNc中GFAP和CD11b增加。中年雌性Rhes KO小鼠在CPu和SNc中表现出TH减少，并且仅在CPu中CD11b增加，但GFAP水平未改变。与雌性Rhes KO小鼠相比，雄性Rhes KO小鼠中更明显的DA神经元变性和神经炎症，在证实Rhes作为DA神经元存活的重要蛋白质的作用的同时，也支持了Rhes KO小鼠作为研究PD中DA神经元变性的脆弱性因素的有价值的临床前模型。
