GUCY2C Signaling Limits Dopaminergic Neuron Vulnerability to Toxic Insults

Authors

Lara Cheslow, Thomas Jefferson UniversityFollow
Matthew Byrne, Thomas Jefferson UniversityFollow
Jessica Kopenhaver, Thomas Jefferson UniversityFollow
Lorraine Iacovitti, Thomas Jefferson UniversityFollow
Richard Smeyne, Thomas Jefferson UniversityFollow
Adam Snook, Thomas Jefferson UniversityFollow
Scott Waldman, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

4-13-2024

Comments

This article is the author's final published version in npj Parkinson's Disease, Volume 10, Issue 1, 2024, Article number 83.

The published version is available at https://doi.org/10.1038/s41531-024-00697-z.

Copyright © The Author(s) 2024

Abstract

Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation within the substantia nigra pars compacta (SNpc) are central drivers of dopaminergic (DA) neuron death in Parkinson's disease (PD). Guanylyl cyclases and their second messenger cyclic (c)GMP support mitochondrial function, protecting against ROS and promoting cell survival in several tissues. However, the role of the guanylyl cyclase-cGMP axis in defining the vulnerability of DA neurons in the SNpc in PD remains unclear, in part due to the challenge of manipulating cGMP levels selectively in midbrain DA neurons. In that context, guanylyl cyclase C (GUCY2C), a receptor primarily expressed by intestinal epithelial cells, was discovered recently in midbrain DA neurons. Here, we demonstrate that GUCY2C promotes mitochondrial function, reducing oxidative stress and protecting DA neurons from degeneration in the 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) mouse model. GUCY2C is overexpressed in the SNpc in PD patients and in mice treated with MPTP, possibly reflecting a protective response to oxidative stress. Moreover, cGMP signaling protects against oxidative stress, mitochondrial impairment, and cell death in cultured DA neurons. These observations reveal a previously unexpected role for the GUCY2C-cGMP signaling axis in controlling mitochondrial dysfunction and toxicity in SNpc DA neurons, highlighting the therapeutic potential of targeting DA neuron GUCY2C to prevent neurodegeneration in PD.

Recommended Citation

Cheslow, Lara; Byrne, Matthew; Kopenhaver, Jessica; Iacovitti, Lorraine; Smeyne, Richard; Snook, Adam; and Waldman, Scott, "GUCY2C Signaling Limits Dopaminergic Neuron Vulnerability to Toxic Insults" (2024). Farber Institute for Neuroscience Faculty Papers. Paper 61.
https://jdc.jefferson.edu/farberneursofp/61

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

38615030

Language

English