A subgroup of spinocerebellar ataxias defective in DNA damage responses

A subgroup of human autosomal recessive ataxias is also characterized by disturbances of eye movement or oculomotor apraxia. These include ataxia telangiectasia (A-T); ataxia telangiectasia like disorder (ATLD); ataxia oculomotor apraxia type 1 (AOA1) and ataxia oculomotor apraxia type 2 (AOA2). What appears to be emerging is that all of these have in common some form of defect in DNA damage response which could account for the neurodegenerative changes seen in these disorders. We describe here sensitivity to DNA damaging agents in AOA1 and evidence that these cells have a defect in single strand break repair. Comparison is made with what appears to be a novel form of AOA (AOA3) which also shows sensitivity to agents that lead to single strand breaks in DNA as well as a reduced capacity to repair these breaks. AOA3 cells are defective in the DNA damage-induced p53 response. This defect can be overcome by incubation with the mdm2 antagonists, nutlins, but combined treatment with nutlins and DNA damage does not enhance the response. We also show that AOA3 cells are deficient in p73 activation after DNA damage. These data provide further evidence that different forms of AOA have in common a reduced capacity to cope with damage to DNA, which may account for the neurodegeneration observed in these syndromes.