GUCY2C signaling limits dopaminergic neuron vulnerability to toxic insults.

Autor:	Cheslow L; Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.; Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA., Byrne M; Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA., Kopenhaver JS; Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA., Iacovitti L; Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA., Smeyne RJ; Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA., Snook AE; Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.; Department of Microbiology & Immunology, Thomas Jefferson University, Philadelphia, PA, USA.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Waldman SA; Department of Pharmacology, Physiology, & Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Oct 13. Date of Electronic Publication: 2023 Oct 13.
DOI:	10.21203/rs.3.rs-3416338/v1
Abstrakt:	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 messengers cyclic (c)GMP, support mitochondrial function, protecting against ROS and promoting cell survival in a number of 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 of neurodegeneration. 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 nigral DA neurons, highlighting the therapeutic potential of targeting DA neuron GUCY2C to prevent neurodegeneration in PD. Competing Interests: Conflicts of Interest: S.A.W. is the CEO, and A.E.S. is a consultant for, Targeted Diagnostics & Therapeutics, Inc. which provided research funding that, in part, supported this work and has a license to commercialize inventions related to this work. The other authors have declared that no conflict of interest exists.
Databáze:	MEDLINE
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