Regulator of G‐protein signaling 6 (RGS6) expression in human substantia nigra pars compacta (SNc) and loss in Parkinson's disease (PD)

Abstract

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by the progressive loss of dopamine (DA) neurons in the SNc. The reason for the greater sensitivity of these neurons to degeneration and their loss with aging in PD is unknown. Although there are treatments targeting symptoms of this disease there are no interventions that protect DA neurons from degeneration. We and our collaborators have recently discovered that RGS6 is restrictively expressed in and required for the adult survival of SNc DA neurons that undergo degeneration in PD. Mice lacking RGS6 exhibit a late onset age‐dependent loss of SNc DA neurons accompanied by reduced striatal and SNc DA content and motor deficits as well as increased sensitivity to 6‐OHDA‐induced neurodegeneration and behavioral deficits. These findings suggest a critical pathogenic link between RGS6 loss and DA neuron degeneration in PD. Here we tested this hypothesis by a quantitative analysis of RGS6 expressing neurons in the SNc of human control and PD patients (n = 5 each). Immunohistochemical analysis of RGS6 and tyrosine hydroxylase (TH) expression and unbiased sterology was used to quantify the numbers of RGS6+ and TH+ SNc neurons. We found that RGS6 is exclusively expressed in DA neurons in the SNc of humans and there is a dramatic (73%) and selective loss of these RGS6+ TH+ neurons in PD patients. Consistent with our hypothesis, all surviving SNc TH+ neurons in normal and PD patients express RGS6. Given our evidence that RGS6 is required for survival of SNc DA neurons in mice, these findings suggest that RGS6 loss in human SNc DA neurons renders them susceptible to neurodegeneration characteristic of PD. These findings provide new evidence suggesting that RGS6 may have a critical neuroprotective role in PD in both mice and humans. Together our findings identify RGS6 as a potential novel therapeutic target for PD treatment.Support or Funding InformationNIH CA161882, MJ Fox 11551