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Shambhu Yadav, PhD



Job Title


Academic Rank

Research Fellow




Shambhu Yadav, Markus Waldeck-Weiermair, Fotios Spyropoulos, Roderick Bronson, Arvind K. Pandey Taylor A Covington, Venkata Thulabandu, Benjamin Steinhorn, and Thomas Michel

Principal Investigator

Thomas Michel

Research Category: Cardiovascular, Diabetes, and Metabolic Disorders


Sensory ataxia and cardiomyopathy caused by neurovascular oxidative stress

Scientific Abstract

Oxidative stress is associated with diverse cardiovascular and neurodegenerative disease states. In these studies, we created and studied transgenic mouse lines that express the yeast enzyme D-amino oxidase (DAAO) in endothelial cells and in neurons. DAAO generates hydrogen peroxide in target tissues only when mice are provided with D-amino acids, causing oxidative stress. The new Cdh5-DAAO-TG mouse expresses DAAO under control of the putatively endothelial-specific Cdh5 promoter. We provided the mice with D-alanine- expecting a vascular phenotype- but discovered that the mice rapidly develop sensory ataxia and are unable to walk. These mice show neurodegeneration in sensory spinal tracts and in dorsal root ganglia (DRG) neurons; motor tracts are normal. We discovered robust transgene expression within DRG neurons; electron microscopy revealed distorted mitochondria. This combination of neuropathy and mitochondrial dysfunction is similar to patients with Friedreich’s ataxia. These patients develop cardiomyopathy; echocardiograms of DAAO-TGCdh5 mouse reveal that they too develop hypertrophic cardiomyopathy. We developed a second transgenic line expressing DAAO under control of a different endothelial cell-specific promoter; this Tie2-DAAO-TG mouse line showed transgene expression in endothelium, but not neurons. The DAAO-TGTie2 mouse does not develop cardiomyopathy. These observations indicate that neuronal oxidative stress is sufficient to cause hypertrophic cardiomyopathy.

Lay Abstract

Oxidative stress plays a vital role in neurodegeneration and cardiovascular diseases. Here we investigated the impact of high oxidative stress in blood vessels and sensory neuronal cells in the mouse model. We created a mouse model that generates hydrogen peroxide in the vasculature and/or sensory neurons that lead to sensory ataxia (movement abnormalities). This new transgenic line expressing functional D-Amino Acid Oxidase in dorsal root ganglia (DRG) and in blood vessels, generate H2O2 in blood vessels and in DRG after feeding D-alanine in drinking water, developed a striking sensory ataxia. The ataxia starts with hind limbs, and rapidly progresses to the forelimbs over the next 2-3 days of D-alanine feeding. Behavior testing confirmed a significant ataxia in D-alanine-treated transgenic mice. Comprehensive pathological analyses reveals a highly specific pattern of neurodegeneration in the dorsal (sensory) tract in the spinal cord and metabolic abnormalities in DRG neuron by electron microscope. All this phenotype seen in these mice is similar to human patients with Friedreich’s ataxia (hereditary ataxia in humans.). Our transgenic mouse represents a robust novel animal model that will lead to a deeper understanding of the roles of neurovascular oxidative stress in the endothelium and dorsal root ganglia in neurogenerative diseases.

Clinical Implications

Our transgenic mouse could be the great animal model that lead to a deeper understanding of the roles of neurovascular oxidative stress in neurodegenerative diseases, and may represent an informative new model of Friedreich’s Ataxia and sensory neurons related diseases.