Progressive sensorimotor impairment is not associated with reduced dopamine and high energy phosphate donors in a model of ataxia‐telangiectasia

Ataxia‐telangiectasia (A‐T) is a genetic disease, associated with progressive motor impairment and a lack of functional ATM protein. It has been reported that immunoreactive tyrosine hydroxylase and dopamine transporter are reduced in an Atm –/– mouse model of A‐T. These observations led to a hypothesis that A‐T is associated with loss of nigrostriatal dopamine and prompted the launch of clinical trials to evaluate a therapeutic utility of the anti‐parkinsonian drug, l ‐DOPA. To test for dopamine depletion more directly, we measured regional levels of monoamines and their metabolites in the Atm –/– mouse brain. We also measured levels of NAD + , a cofactor for dopamine biosynthesis and substrate of the DNA damage surveillance enzyme, poly(ADP‐ribose) polymerase (PARP). Constitutive activation of PARP has been posited to cause NAD + depletion. We observed no reduction in monoamine transmitters and no depletion of NAD + , or other high energy phosphate donors in the adult Atm –/– cerebellum, striatum, or ventral mesencephalon. However, our studies did reveal a progressive sensorimotor impairment in Atm –/– mice that may serve as a relevant proxy for progressive neurological impairment in the human disease. Our results call into question the involvement of dopamine in A‐T and the therapeutic strategy of enhancing dopaminergic function with l ‐DOPA.