Neuroprotection by the GUCY2C gut-brain axis in Parkinson's disease

Thomas Jefferson University, Philadelphia PA

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Abstract

Parkinson’s disease (PD) is the second most common cause of age-related neurodegeneration in the U.S. In PD, mitochondrial dysfunction in midbrain dopamine (DA) neurons in the substantia nigra (SN) induces oxidative stress and cell death. In turn, this neurodegeneration leads to DA depletion, which underlies the motor dysfunction and dementia that are hallmarks of this disease. Current therapies raise DA 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 DA neurons from degeneration to prevent and treat PD. Guanylyl cyclase C (GUCY2C) is an intestinal receptor for locally-produced hormones that regulate secretion, the basis for approval of the GUCY2C agonist linaclotide to treat constipation. In intestine, this receptor signaling axis also supports mitochondrial biogenesis through the transcriptional coactivator PGC1α, and its disruption produces mitochondrial dysfunction central to the pathophysiology of cancer; inflammatory bowel disease; and toxic injury. Recently, the GUCY2C hormone axis emerged as the afferent limb of endocrine pathways controlling two discreet circuits in brain. GUCY2C in neurons in the hypothalamic ventral premammillary nucleus controls leptin signaling regulating appetite. Disrupting this gut-brain endocrine axis contributes to hyperphagia underlying obesity. Further, GUCY2C is expressed by DA neurons in the SN, where it plays a role in memory and behavior. Our preliminary studies suggest that GUCY2C supports mitochondrial biogenesis protecting DA neurons in the SN from toxic insults. Thus, silencing GUCY2C amplifies DA neuron degeneration in the SN induced by MPTP, a mitochondrial toxin that selectively kills DA neurons. This DA neuron toxicity is associated with depletion of DA and its metabolites from the striatum, and induction of inflammation and reactive gliosis in the SN. Moreover, silencing GUCY2C in DA neurons depletes mitochondria, and their associated electron transport complexes, from the SN, characteristic of toxic insults in PD. These preliminary studies suggest a model in which the GUCY2C-signaling axis controls midbrain vulnerability to toxic insults by supporting mitochondrial biogenesis protecting DA neurons in the SN. Studies here explore two novel hypotheses. The Therapeutic Hypothesis suggests that toggling GUCY2C in the midbrain “OFF” (genetically), or “ON” (linaclotide stimulation) modulates the vulnerability of DA neurons to toxic degeneration. The Mechanistic Hypothesis suggests that GUCY2C protects the integrity of SN DA neurons through PGC1α- dependent mitochondrial biogenesis. These studies will reveal a therapeutic target (midbrain GUCY2C), a mechanism (mitochondrial biogenesis) that may be generalizable to the spectrum of toxic insults in the midbrain, and a specific therapeutic paradigm (linaclotide) to prevent midbrain DA neurodegeneration. The potential to translate these studies into new strategies to prevent and treat PD can best be appreciated by considering that the GUCY2C agonists linaclotide and plecanatide are FDA-approved to treat chronic constipation syndromes.