Rhes Counteracts Dopamine Neuron Degeneration and Neuroinflammation Depending on Gender and Age

Abstract

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.

Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age

“…The present results are also in line with previous findings showing that MDMA may induce neuroinflammatory and toxic effects in a gender-dependent manner and that males are more susceptible to these effects [50,51,52]. Although the results obtained in the present study confirm that Rhes signaling pathways are implicated in glial activation and neuronal survival [6,10,51,52,53,54], the mechanism that forms the basis of glial activation and DA neuron degeneration in Rhes KO mice must be elucidated by further studies.…”

“…Moreover, evaluation of the relationship between this decrease and gender revealed a further important result by showing that adult male Rhes KO mice showed a marked decrease, especially in STR and SNc, whereas female Rhes KO mice did not. This result is in line with our previous paper which reported that in basal conditions, adult male Rhes KO mice displayed a significant decrease in TH-positive fibres in STR compared with WT mice, whereas no modifications were observed in adult female Rhes KO mice compared with WT mice [10].…”

“…Starting from results of our research group showing that adult and middle-aged Rhes KO mice develop a spontaneous and age-dependent increase in astroglial and microglial cells, in both STR and SNc, which was more marked in male than in female mice [10], the present study examined the role of Rhes protein on the effects of the psychostimulant drug MDMA on GFAP and CD11b and evaluated if its effects were influenced by age and gender. Results show that glial activation in the nigrostriatal and mesocortical systems in response to MDMA administration is increased in Rhes KO adult male mice as compared with WT mice only in selective cases (GFAP in STR and CD11b in SNc), while decrease in TH in KO mice was observed in most cases.…”

“…In a recent study, our laboratory investigated the contribution of Rhes to neuroinflammation, demonstrating that lack of Rhes caused an increase of astrogliosis and microgliosis in KO mice [10]. These findings are particularly important since epidemiological and experimental evidence indicate that, among the possible etiopathogenic factors, neuroinflammation is one of major driver for progression of psychiatric disorders such as schizophrenia [11,12,13].…”

Parkinson’s Disease in Women and Men: What’s the Difference?

“…Accordingly, reserpine-treated female rats did not show any reduction of tyrosine hydroxylase immunoreactivity in the SNc and dorsal striatum compared to males [90]. The lack of Ras homolog enriched in striatum (Rhes), a protein that exert pleiotropic effects on cell function, in KO mice induced a decrease in tyrosine hydroxylase expression in males only, while KO females showed resistance to DA neuron degeneration, which tended to decrease only with aging [91,92]. Interestingly, neuronal loss in male SNc is accompanied by a significant reduction in total ganglioside content, especially neuronal-or synaptic-enriched gangliosides GD1a and GT1b.…”