PROJECT SUMMARY/ABSTRACT Parkinson’s disease is the second most common cause of age-related neurodegeneration in the U.S. In Parkinson’s disease, mitochondrial dysfunction in midbrain dopaminergic neurons in the substantia nigra induces oxidative stress and cell death. In turn, this neurodegeneration leads to dopamine depletion, which underlies the motor dysfunction and dementia that are hallmarks of this disease. Current therapies raise dopamine levels to relieve motor symptoms, but do not prevent neurodegeneration, disease progression, or death. Thus, there is an essential unmet need to develop novel therapeutic strategies that protect dopaminergic neurons from degeneration to prevent and treat Parkinson’s disease. Guanylyl cyclase C (GUCY2C) is the intestinal receptor for the hormone uroguanylin produced in intestine, with a canonical role in fluid and electrolyte balance. In intestine, this paracrine axis supports mitochondrial structure and function, and its disruption, universally reflecting hormone loss, is central to the pathophysiology of cancer; inflammation and autoimmunity; and toxic injury. Recently, uroguanylin emerged as the afferent limb of endocrine axes controlling two discrete circuits in brain. GUCY2C in neurons in the hypothalamic ventral premamillary nucleus controls leptin signaling regulating satiety and body weight. Disrupting this gut-brain endocrine axis contributes to hyperphagia underlying obesity. Further, GUCY2C is expressed by dopaminergic neurons in the substantia nigra, although its (patho)physiological function remains undefined. Our preliminary studies reveal that silencing GUCY2C increases the vulnerability of dopaminergic neurons in the substantia nigra in mice to degeneration induced by MPTP, a mitochondrial toxin that selectively kills dopaminergic neurons in the substantia nigra in rodents, primates, and humans. Moreover, GUCY2C signaling supports the mitochondrial transcriptome central to preventing Parkinson’s disease, and silencing GUCY2C causes a significant loss of mitochondrial protein within the substantia nigra. These preliminary studies suggest a model in which the GUCY2C-uroguanylin gut-brain endocrine axis controls midbrain vulnerability to toxic insults by maintaining mitochondrial integrity to protect dopaminergic neurons in the substantia nigra. Thus, studies here explore the novel Physiological Hypothesis that uroguanylin secreted by intestine and GUCY2C expressed in the midbrain form a novel endocrine gut-brain axis that protects dopaminergic neurons, opposing toxic degeneration. The Mechanistic Hypothesis suggests that GUCY2C protects the integrity of midbrain dopaminergic neurons by supporting mitochondrial structure and function. The Therapeutic Hypothesis suggests that exogenous GUCY2C ligands protect midbrain dopaminergic neurons from toxic insults, potentially opposing the development and progression of Parkinson’s disease. The possibility of translating these studies into new therape...