The <scp>S</scp>mall <scp>GTP</scp>‐<scp>B</scp>inding <scp>P</scp>rotein <scp>R</scp>hes <scp>I</scp>nfluences <scp>N</scp>igrostriatal‐<scp>D</scp>ependent <scp>M</scp>otor <scp>B</scp>ehavior <scp>D</scp>uring <scp>A</scp>ging

Pinna, Annalisa; Napolitano, Francesco; Pelosi, Barbara; Maio, Anna; Wardas, Jadwiga; Casu, Maria Antonietta; Costa, Giulia; Migliarini, Sara; Calabresi, Paolo; Pasqualetti, Massimo; Morelli, Micaela; Usiello, Alessandro

doi:10.1002/mds.26489

Cited by 14 publications

(25 citation statements)

References 23 publications

(49 reference statements)

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“…It was previously shown that lack of Rhes leads to a decrease of nigral TH-positive neurons accompanied by motor coordination deficits in male mice (Pinna et al, 2016 ). The present study provides insight into the factors contributing to neurodegeneration in Rhes KO mice by demonstrating that, besides the DAergic neurodegeneration, an increase in astrogliosis and microgliosis is present in these KO mice.…”

Section: Discussionmentioning

confidence: 97%

“…Rhes mRNA is localized in striatal GABAergic medium-sized projection neurons of rodents and humans (Errico et al, 2008 ; Ghiglieri et al, 2015 ; Vitucci et al, 2015 ) and in large aspiny cholinergic interneurons (Sciamanna et al, 2015 ), where it modulates dopamine (DA)-dependent transmission. Recently, we have shown that Rhes mRNA is also expressed, although to a lesser extent, in tyrosine hydroxylase (TH)-positive neurons of the SNc and ventral tegmental area of the mouse midbrain (Pinna et al, 2016 ). Consistent with Rhes mRNA midbrain localization and its putative protective role in DAergic cell survival, male Rhes knockout (KO) mice have shown a reduction in TH-positive neurons in the SNc, associated with a progressive deficit in motor coordination and balance (Pinna et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have shown that Rhes mRNA is also expressed, although to a lesser extent, in tyrosine hydroxylase (TH)-positive neurons of the SNc and ventral tegmental area of the mouse midbrain (Pinna et al, 2016 ). Consistent with Rhes mRNA midbrain localization and its putative protective role in DAergic cell survival, male Rhes knockout (KO) mice have shown a reduction in TH-positive neurons in the SNc, associated with a progressive deficit in motor coordination and balance (Pinna et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…Considering the influence of Rhes on the survival of nigrostriatal DAergic neurons (Pinna et al, 2016 ), and the differential incidence of PD between men and women (Gillies et al, 2014 ; Labandeira-Garcia et al, 2016 ), in the present study, we investigated the possible presence of neurotoxic and neuroinflammatory events in male and female Rhes KO mice at different ages. Neurodegeneration was assessed by means of immunoreactivity of TH, the enzyme involved in the synthesis of DA, whereas neuroinflammation was evaluated by measuring microgliosis and astrogliosis through immunoreactivity for complement type 3 receptor (CD11b) and GFAP respectively, in the CPu and SNc.…”

Section: Introductionmentioning

confidence: 99%

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

Costa

Pinna

Porceddu

et al. 2018

Front. Aging Neurosci.

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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.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Costa

Pinna

Porceddu

et al. 2018

Front. Aging Neurosci.

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show abstract

“…A further support for a possible link between Rhes and Parkinson’s disease comes from recent findings indicating that this small GTPase is also expressed in a subset of tyrosine hydroxylase-positive neurons of the substantia nigra pars compacta, where its genetic ablation enhances vulnerability to age-dependent neuronal death in mutant mice [45]. Although the specific mechanism underpinning the relationship between Rhes and the survival of dopaminergic neurons is not clear, previous studies demonstrating its binding to beclin-1 [46] suggest a potential involvement of this G protein in cellular events implicated in neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Decreased Rhes mRNA levels in the brain of patients with Parkinson’s disease and MPTP-treated macaques

et al. 2017

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In rodent and human brains, the small GTP-binding protein Rhes is highly expressed in virtually all dopaminoceptive striatal GABAergic medium spiny neurons, as well as in large aspiny cholinergic interneurons, where it is thought to modulate dopamine-dependent signaling. Consistent with this knowledge, and considering that dopaminergic neurotransmission is altered in neurological and psychiatric disorders, here we sought to investigate whether Rhes mRNA expression is altered in brain regions of patients with Parkinson’s disease (PD), Schizophrenia (SCZ), and Bipolar Disorder (BD), when compared to healthy controls (about 200 post-mortem samples). Moreover, we performed the same analysis in the putamen of non-human primate Macaca Mulatta, lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Overall, our data indicated comparable Rhes mRNA levels in the brain of patients with SCZ and BD, and their respective healthy controls. In sharp contrast, the putamen of patients suffering from PD showed a significant 35% reduction of this transcript, compared to healthy subjects. Interestingly, in line with observations obtained in humans, we found 27% decrease in Rhes mRNA levels in the putamen of MPTP-treated primates. Based on the established inhibitory influence of Rhes on dopamine-related responses, we hypothesize that its striatal downregulation in PD patients and animal models of PD might represent an adaptive event of the dopaminergic system to functionally counteract the reduced nigrostriatal innervation.

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Positive relation between dopamine neuron degeneration and metabolic connectivity disruption in the MPTP plus probenecid mouse model of Parkinson's disease

Tassan Mazzocco,

Serra,

Maspero

et al. 2024

Experimental Neurology

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The Small GTP‐Binding Protein Rhes Influences Nigrostriatal‐Dependent Motor Behavior During Aging

Abstract: Our findings indicate a fine-tuning role of Rhes in regulating the number of TH-positive neurons of the substantia nigra and nigrostriatal-sensitive motor behavior during aging.

Cited by 14 publications

References 23 publications

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

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

Decreased Rhes mRNA levels in the brain of patients with Parkinson’s disease and MPTP-treated macaques

Positive relation between dopamine neuron degeneration and metabolic connectivity disruption in the MPTP plus probenecid mouse model of Parkinson's disease

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