Sensory ataxia and cardiomyopathy caused by neurovascular oxidative stress

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.