Thomas Kuret, MS

Parkinson’s disease (PD), the 2nd most common neurodegenerative disorder, reflects mitochondrial dysfunction, oxidative stress, and dopamine (DA) neuron death in the midbrain. Therapies replace dopamine to relieve symptoms without slowing neuron death, highlighting the need for drugs that block disease progression. We discovered that DA neuron GUCY2C blocks toxin-induced mitochondrial dysfunction and neurotoxicity in a mouse model of PD. Here, we will expand these studies to explore the utility of GUCY2C to block mitochondrial dysfunction and neurotoxicity induced by prevalent PD insults, including SARS-CoV-2 or a-synuclein, in mice. We propose a Pathophysiological Hypothesis in which GUCY2C protects DA neuron integrity, a Mechanistic Hypothesis in which GUCY2C opposes neurotoxicity by supporting mitochondrial function, and a Therapeutic Hypothesis in which activating GUCY2C with FDA-approved agonists prevents DA neuron loss. Success will permit repurposing of these drugs to treat PD.