MUTANT AP ENDONUCLEASE IN PATIENTS WITH AMYOTROPHIC-LATERAL-SCLEROSIS

AMONG the more frequent oxidative DNA injuries is the formation of aba sic sites (AP sites) resulting from removal of purine or pyrimidine ba ses, estimated to occur at a rate of 1 x 10(4)/genome/24 h. A defect i n DNA repair at this level could account for the accumulation of mutat ions and subsequent genome instability. We have identified missense mu tations in the APE gene coding for a multifunctional DNA repair enzyme , AP endonuclease in eight of 11 patients with amyotrophic lateral scl erosis (ALS) and familial ALS. These mutations could affect the repair of abasic sites leading to the accumulation of mutations in neurons, resulting in their degeneration and death. Our findings implicate muta ted AP endonuclease in the pathogenesis of ALS.