Regulator of G protein Signaling 6 (RGS6) Suppresses Late‐age‐onset Nigral Dopaminergic Neurodegeneration, α‐Synuclein Accumulation and Motor Dysfunction

Abstract

Parkinson's disease (PD) is devastating, primarily non‐familial, age‐related neurodegenerative disorder caused by the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Why these neurons die with aging in sporadic PD is unknown. However, accumulation of α‐synuclein aggregates in Lewy bodies is believed to play a crucial role in PD pathogenesis. In support of this hypothesis, cAMP‐elevating β‐agonists dramatically reduce both α‐synuclein expression and the incidence of human PD as well as repress MPTP‐induced SNc DA neuron loss in mice (Mittal et al., Science 2017). Neuronal cAMP levels are controlled by neurotransmitter GPCRs coupled to Gs or Gi/o which stimulate or inhibit adenylyl cyclases (AC), respectively. RGS proteins powerfully modulate signaling by GPCRs including DA receptors. Remarkably, we have recently discovered that RGS6 is restrictively expressed in human SNc DA neurons that are lost in PD and knockout of RGS6 in mice recapitulates key hallmarks of sporadic PD, including: late‐age‐onset SNc DA neuron degeneration, reduced nigrostriatal DA, and motor deficits. We also demonstrated that RGS6 functions as a critical negative regulator of SNc D2 autoreceptor signaling allowing for proper modulation of DA‐dependent motor behaviors. Given that β‐agonists repress α‐synuclein expression through their activation of β2‐adrenorecetor‐Gαs, a GPCR that increases cAMP, and RGS6's role in inhibiting D2 autoreceptor signaling, a Gi/o GPCR that reduces cAMP, we hypothesize that RGS6, like β‐agonists, may function to prevent the pathological accumulation of α‐synuclein through modulation of cAMP‐PKA signaling. Here we show that RGS6 is a key negative modulator of Gi/o signaling in SNc DA neurons, with its loss provoking enhance D2 autoreceptor activity and a subsequent reduction in cAMP‐PKA signaling. These data are important as cAMP‐PKA signaling has not only been linked to SNc DA neuron survival in PD but also pathological α‐synuclein accumulation. In agreement with these previous reports, we observed elevated SNc α‐synuclein protein expression in 12 and 18mo RGS6−/− mice relative to RGS6+/+ controls. The aberrant elevation in α‐synuclein expression in the SNc of RGS6−/− mice was accompanied by a transition in α‐synuclein expression patterns from largely intracellular, as seen in RGS6+/+ mice, to largely extracellular. Furthermore, western blot analysis revealed increased expression of oligomeric α‐synuclein isoforms in the SNc of RGS6−/− mice, another hallmark of PD pathophysiology. Together, these data identify RGS6 as a key G protein regulator that protects against PD‐related neurodegeneration and α‐synuclein pathology through inhibition of D2R‐Gi/o signaling in SNc DA neurons.Support or Funding InformationNIH AA025919 and Interdisciplinary Research Fellowship T32HL007121This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.