Nigral dopamine (DA) neurons are extremely sensitive to inflammatory stimuli; therefore, chronic neuroinflammation has been implicated in the pathogenesis of Parkinson's disease. In support of this, epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) lowers the risk for development of PD. Therefore, identification of key molecular regulators of neuroinflammation and/or the sensitivity of dopamine neurons to inflammation-induced death is likely to reveal novel targets for drug development to halt, delay or prevent PD.
Our preliminary studies suggest a protective role for Regulator of G-protein Signaling-10 (RGS10) during inflammatory responses in the brain. Loss of RGS10 results in overproduction of toxic inflammatory cytokines (such as TNF) and increases the vulnerability of nigral DA neurons to inflammation-induced degeneration.
We will investigate the extent to which overexpression of RGS10 via viral delivery affords neuroprotection in a pre-clinical model of PD, and perform cell culture experiments to identify the molecular mechanisms mediating its neuroprotective actions. We expect that elevated levels of RGS10 in DA neurons and/or microglia will rescue nigral DA neurons from neurotoxic insults and modulate the accompanying neuroinflammatory reaction in the ventral midbrain. It is possible, however, that the efficacy of protection and the mechanism(s) by which RGS10 exerts its function(s) in the two cell types will differ. Regardless of the mechanism underlying enhanced DA cell survival, overexpression of RGS10 can simply serve as a tool to ensure a better functional outcome to neurotoxic insults.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Age-related inflammation in the brain may contribute to increased vulnerability to inflammation-induced nigral degeneration and development of PD through downregulation of RGS10, dysregulation of microglial activation responses, and a self-propelling cycle of neuroinflammation in the midbrain. If overexpression of RGS10 renders the nigrostriatal pathway less vulnerable to oxidative stress and inflammatory stimuli, RGS10 would emerge as a potential therapeutic target for blocking or delaying the progressive loss of nigrostriatal dopaminergic neurons in patients with early signs of PD.
We hope to learn whether overexpressing RGS10 in a rodent model of PD is protective.