Role Of Regulator Of G Protein Signaling5(Rgs5) In Immune-regulation Of Central Nervous System

Parkinson’s disease (PD) is one of the most common neurodegenerative diseasesin the central nervous system. It is characterized by slow and progressivedegeneration of dopaminergic neurons in the substantia nigra pars compact (SNc).Accumulating evidence indicates that many processes contribute to the diseaseprogression such as α-synuclein accumulation, oxidative stress, mitochondriadysfunction, and dysregulation of ubiquitin-proteasome system. Results fromepidemiological, neurogenetic and post-mortem studies showed that the levels ofneuroinflammation increased with ageing and contributed to neurodegenearation.However, the molecular mechanisms regulating the inflammatory reactions in thecentral nervous system are still largely unknown. Here, we find that Rgs5may bean important regulator of astrocytic responses to immune stimuli in vivo and in vitro.Comparing with littermate controls, the levels of interleukin1beta (IL-1β) weresignificantly increased in Rgs5knockout (KO) mice. Rgs5KO astrocytes alsoshowed stronger responses after tumor necrosis factor alpha (TNF-α) stimulation in primary cultures. In MPTP model of Parkinson’s disease, midbrain dopamineneurons showed increased vulnerability in Rgs5KO mice. In conclusion, our datasuggests that astrocyte-derived Rgs5may play important roles in the regulation ofneuroinflammation and is a promising target for disease intervention.AIM: To investigate the possible participation of Rgs5in the regulation ofneuroinflammation and selective degeneration of dopaminergic neurons in PD.METHODS:1. PD models were induced by MPTP administration both in wild-typemice and KO mice in which global Rgs5null mice and condition knockout (Rgs5f/f;CD11b-Cre+and Rgs5f/f; hGFAP-Cre+) mice were included.2. Dopaminergic neurons,astrocytes and microglia were detected by immunostaining of tyrosine hydroxylase(TH), glial fibrillary acidic protein (GFAP), and ionized calcium binding adaptormolecule1(Iba1), respectively.3. Survival rate of primary cultured midbraindopamine neurons was measured by cell counting after neurotoxin MPP+exposure.4. Expression levels of inflammatory cytokines of TNF--stimulated primaryastrocytes were analyzed by western blotting and qPCR.RESULTS:1. The protein level of IL-1β was increased in the striatum of Rgs5KO mice,although there was no difference in the mRNA levels of IL-1β, IL-12β andTNF-. Similar phenomenon was observed in cultured astrocytes from controlmice and Rgs KO mice.2. In the MPTP model of PD, Rgs5deficiency exacerbated the loss ofdopaminergic neurons.3. No difference was detected in the survival rate of primary cultured midbrain dopamine neurons from wild-type and Rgs5null mice after neurotoxin MPP+administration.4. IL-1β was up-regulated both in the protein and mRNA levels in primarycultured astrocytes after TNF-stimulation.CONCLUSION: Rgs5may regulate neuroinflammation and contribute toneurodegeneration in PD.