park+/+ and park-/- Drosophila have sexually dimorphic brain redox chemistry

Authors

Amber N. Juba, Biomedical Sciences Program, Midwestern University, Glendale, AZ 85308, USA.
Bobbi Stwalley, Biomedical Sciences Program, Midwestern University, Glendale, AZ 85308, USA.
Tigran Margaryan, Department of Translational Neuroscience, Ivy Brain Tumor Center at Barrow Neurological Institute, Phoenix, AZ 85013, USA.
Riley Hamel, Department of Anatomy, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA.
Amanda N. Foley, Department of Anatomy, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA.
T Bucky Jones, Department of Anatomy, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA.
Artak Tovmasyan, Department of Translational Neuroscience, Ivy Brain Tumor Center at Barrow Neurological Institute, Phoenix, AZ 85013, USA.
Lori M. Buhlman, Biomedical Sciences Program, Midwestern University, Glendale, AZ 85308, USA.

Document Type

Article

Abstract

Sexual dimorphism in Parkinson's disease (PD) pathophysiology is poorly understood. Elucidating consequences of disease-causing mutations on brain redox chemistry may reveal therapeutic targets for all people with PD. We report that male Drosophila had increased hydrogen peroxide and glutathione (G-SH) redox disequilibrium in vulnerable dopaminergic neuron mitochondria. Levels of cysteine and oxidized cystine were decreased, with cysteine/cystine ratios (indicating less oxidative stress) and G-SH levels being elevated in parkin-null (park-/-) Drosophila brains, and more so in males. We report effects of parkin loss and sex on the levels of low-molecular-weight thiols involved in G-SH synthesis, providing clues as to mechanisms implicated in altered levels of brain G-SH, cysteine and cystine. Protein nitration was decreased in the brain of park-/- flies, especially in females, suggesting that decreased nitric oxide levels compensate for loss of parkin or lack of protective nitric oxide synthase activity. Our results imply that park-/- flies have elevated levels of G-SH that meet antioxidant demand in the absence of parkin in the whole brain, but not in vulnerable neurons. Identification of sexually dimorphic PD risk factors could inform symptom management and highlight sex-specific therapeutic strategies.

Keywords

Drosophila, Antioxidants, Dopaminergic neuron, Glutathione, Hydrogen peroxide, Mitochondria, Oxidative stress, Parkin, Parkinson's disease, Redox, Sex, Sexual dimorphism

Medical Subject Headings

Animals; Ubiquitin-Protein Ligases (metabolism, deficiency); Male; Oxidation-Reduction; Female; Drosophila Proteins (metabolism); Drosophila melanogaster (metabolism); Sex Characteristics; Brain (metabolism); Mitochondria (metabolism); Dopaminergic Neurons (metabolism); Glutathione (metabolism); Oxidative Stress; Brain Chemistry; Hydrogen Peroxide (metabolism); Cysteine (metabolism); Sulfhydryl Compounds (metabolism)

Publication Date

8-1-2025

Publication Title

Disease models & mechanisms

E-ISSN

1754-8411

Volume

18

Issue

8

PubMed ID

40827381

Digital Object Identifier (DOI)

10.1242/dmm.052250

Recommended Citation

Juba, Amber N.; Stwalley, Bobbi; Margaryan, Tigran; Hamel, Riley; Foley, Amanda N.; Jones, T Bucky; Tovmasyan, Artak; and Buhlman, Lori M., "park+/+ and park-/- Drosophila have sexually dimorphic brain redox chemistry" (2025). Translational Neuroscience. 2473.
https://scholar.barrowneuro.org/neurobiology/2473