Parkinson’s Disease Therapies Targeting GUCY2C
Parkinson’s disease (PD) is the second most common cause of age-related neurodegeneration in the United States. In PD, mitochondrial dysfunction within dopaminergic (DA) neurons of the substantia nigra (SN) induces DA neuron death, causing subsequent DA depletion and motor dysfunction. Current therapies for PD patients raise DA levels to temporarily relieve motor symptoms, but do not prevent further DA neurodegeneration or slow disease progression. Thus, there is an unmet need to develop novel therapies that protect DA neurons to treat PD. Guanylyl cyclase C (GUCY2C) is the intestinal and neural receptor for uroguanylin (GUCA2B), a hormone produced primarily in the small intestine. Within the intestine, GUCY2C-GUCA2B signaling protects mitochondrial function, and disruption of this signaling axis, reflecting the loss of hormone GUCA2B, is central to gastrointestinal cancer, autoimmunity, and toxic injury. More recently, neural GUCY2C – expressed in the hypothalamus and SN – and intestinal GUCA2B have emerged as key players in novel gut-brain signaling axes. In the hypothalamus, where GUCY2C is expressed by neurons regulating appetite, we have demonstrated that GUCY2C-GUCA2B signaling promotes healthy satiety. However, the role that this gut-brain axis plays in the SN, where GUCY2C is expressed by DA neurons that are lost in PD, remains undefined. Our preliminary studies suggest that the GUCY2C-GUCA2B axis protects DA neurons against cell death through promoting mitochondrial health. Our proposed research seeks to explore this signaling axis in greater depth and to investigate the potential of medication that stimulates neural GUCY2C to protect DA neurons from further degeneration in PD patients. The potential to translate these studies into new drugs to treat and prevent PD can be appreciated by considering that the GUCY2C ligands linaclotide and plecanatide are FDA-approved to treat constipation.
Receiving a fellowship from the Foundation has allowed me to pursue our lab’s interest in the gut-brain axis within the context of Parkinson’s disease. This award has opened the door to utilizing the latest techniques, equipment, and analyses to gain a holistic understanding of the molecular mechanisms driving mitochondrial dysfunction and neurodegeneration.