Parkinson's disease (PD) is the second most common neurodegenerative disease in the U.S. The coremotor symptoms of PD are attributable to the degeneration of dopamine (DA) neurons in the substantianigra pars compacta (SNc). Why SNc DA neurons die in PD has been an enduring mystery. Inthe last grant period, we made significant progress toward identifying characteristics of these neurons thatcould lead to their accelerated aging, dysfunction and death. These studies suggest that the selectivevulnerability of SNc DA neurons in PD is linked to their reliance upon Cavi.3 Ca2+ channelsto i) drive autonomous pacemaking and 2) generate spike bursts in response to synapticstimulation. More importantly from the the therapeutic standpoint, we discovered that this reliance uponCavi.3 channels could be diminished by systemic administration of a drug that is approved for human use inthe treatment of hypertension. In a murine model, treatment with this drug led to significant protection ofSNc DA neurons against rotenone toxicity in vitro and against 6-OHDA and MPTP in vivo. The central aimof this project is to determine the mechanisms underlying these observations and to lay thefoundation for translating these bench discoveries into a plan for clinical neuroprotection trialsin humans. Using the most advanced optical, electrophysiological and molecular tools available, ourinterdisciplinary research team (Drs. Surmeier, Wilson, Bevan and Osten) will pursue four specific aims:1) to characterize the interaction between mitochondria and the Ca24' that enters SNc DA neurons duringpacemaking (Surmeier, Wilson).2) to characterize the impact of glutamatergic synaptic input on mitochondrial function during pacemakingin SNc DA neurons (Bevan, Surmeier, Osten)3) to characterize the mechanisms underlying the reversion of pacemaking in SNc DA neurons followingsustained block of Cavi.3 channels (Surmeier, Osten).4) to explore novel neuroprotective strategies targeting Cavi.3 channels in SNc DA neurons that could betranslated to human clinical trials (Surmeier, Osten).The successful attainment of these aims will move us closer to clinical neuroprotection trials and provideneeded insight into the cellular and molecular mechanisms underlying the loss of SNc DA neurons in PD.Lay summary: Understanding why neurons die in PD will help us stop the disease. These studies take thesteps necessary to bring a novel neuroprotective therapy to the clinic in the near term.
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