Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress in chemogenetic transgenic mouse lines

Shambhu Yadav, Markus Waldeck-Weiermair, Fotios Spyropoulos, Roderick Bronson, Arvind K. Pandey, Apabrita Ayan Das, Alexander C. Sisti, Taylor A. Covington, Venkata Thulabandu, Shari Caplan, William Chutkow, Benjamin Steinhorn and Thomas Michel ()
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Shambhu Yadav: Brigham and Women’s Hospital, Harvard Medical School
Markus Waldeck-Weiermair: Brigham and Women’s Hospital, Harvard Medical School
Fotios Spyropoulos: Brigham and Women’s Hospital, Harvard Medical School
Roderick Bronson: Harvard Medical School
Arvind K. Pandey: Brigham and Women’s Hospital, Harvard Medical School
Apabrita Ayan Das: Brigham and Women’s Hospital, Harvard Medical School
Alexander C. Sisti: Brigham and Women’s Hospital, Harvard Medical School
Taylor A. Covington: Brigham and Women’s Hospital, Harvard Medical School
Venkata Thulabandu: Brigham and Women’s Hospital, Harvard Medical School
Shari Caplan: Novartis Institutes for Biomedical Research
William Chutkow: Novartis Institutes for Biomedical Research
Benjamin Steinhorn: Brigham and Women’s Hospital, Harvard Medical School
Thomas Michel: Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Oxidative stress is associated with cardiovascular and neurodegenerative diseases. Here we report studies of neurovascular oxidative stress in chemogenetic transgenic mouse lines expressing yeast D-amino acid oxidase (DAAO) in neurons and vascular endothelium. When these transgenic mice are fed D-amino acids, DAAO generates hydrogen peroxide in target tissues. DAAO-TGCdh5 transgenic mice express DAAO under control of the putatively endothelial-specific Cdh5 promoter. When we provide these mice with D-alanine, they rapidly develop sensory ataxia caused by oxidative stress and mitochondrial dysfunction in neurons within dorsal root ganglia and nodose ganglia innervating the heart. DAAO-TGCdh5 mice also develop cardiac hypertrophy after chronic chemogenetic oxidative stress. This combination of ataxia, mitochondrial dysfunction, and cardiac hypertrophy is similar to findings in patients with Friedreich’s ataxia. Our observations indicate that neurovascular oxidative stress is sufficient to cause sensory ataxia and cardiac hypertrophy. Studies of DAAO-TGCdh5 mice could provide mechanistic insights into Friedreich’s ataxia.

Date: 2023
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DOI: 10.1038/s41467-023-38961-0

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