Project 2:
TRPC1, Calcium and Parkinson’s Disease
Investigator: Dr. Brij Singh

Parkinson's disease (PD), the second most common neurodegenerative disorder, at least in part is caused by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. While the underlying causes of dopaminergic cell death or the molecular mechanisms by which these neurons degenerate are still not fully understood, several molecular mechanisms have been proposed to play a role. These include overproduction of reactive oxygen species, impairment of mitochondrial function, disturbances of Ca²⁺ homeostasis, and excitotoxicity. Of these, Ca²⁺ homeostasis may be the most important because Ca²⁺ has both stimulatory and inhibitory effects on cell death processes and Ca²⁺ is a common link between reactive oxygen species generation, mitochondrial dysfunction, and apoptosis. Our recent data suggest that transient receptor potential protein -1 (TRPC1) functions as a plasma membrane Ca²⁺ channel in dopaminergic neurons and the expression/localization of TRPC1 was inhibited/altered by drugs used as a model to cause PD (Bollimuntha et al., 2005; 2006). However, little is known about the molecular mechanism(s) exerted by TRPC1 in PD and no data are available on the role of impaired Ca²⁺ influx upon loss of TRPC1 in dopaminergic neurodegeneration. Thus, it is important to characterize TRPC1 channel activity and define the molecular pathways involved in the onset and/or progression of PD. Our central hypothesis is that TRPC1 protects dopaminergic neurons by inhibiting apoptotic mediated cell death and by restoring mitochondrial function. Our preliminary results suggest that treatments causing PD (MPP⁺ or salsolinol), decrease TRPC1 protein levels, its plasma membrane localization, and its Ca²⁺ influx capabilities. Conversely, overexpression of TRPC1 in SH-SY5Y dopaminergic neuronal cells protected against apoptotic cell death induced by MPP⁺ or salsolinol. The rationale for these studies is that detailed characterization of TRPC1 and elucidation of the mechanisms by which it exerts neuroprotection will be important to understand the pathophysiology of PD and to gain insight into possible therapeutics. This research is innovative because it will characterize the role of TRPC1 in PD, and will identify the signaling mechanisms essential for neuronal function and survival. Upon completion of this project we anticipate having elucidated the mechanisms by which TRPC1 protects degeneration of dopaminergic neurons. This information will help others and us to explore potential therapeutic interventions/strategies to treat Parkinson’s patients; unfortunately current therapeutics are of limited effectiveness.