Several different autosomal recessive genetic disorders characterized by ataxia with oculomotor apraxia (AOA) have been identified with the unifying feature of defective DNA damage recognition and/or repair. We describe here the characterization of a novel form of AOA showing increased sensitivity to agents that cause single-strand breaks (SSBs) in DNA but having no gross defect in the repair of these breaks. Evidence for the presence of residual SSBs in DNA was provided by dramatically increased levels of poly (ADP-ribose)polymerase (PARP-1) auto-poly (ADP-ribosyl)ation, the detection of increased levels of reactive oxygen/nitrogen species (ROS/RNS) and oxidative damage to DNA in the patient cells. There was also evidence for oxidative damage to proteins and lipids. Although these cells were hypersensitive to DNA damaging agents, the mode of death was not by apoptosis. These cells were also resistant to TRAIL-induced death. Consistent with these observations, failure to observe a decrease in mitochondrial membrane potential, reduced cytochrome c release and defective apoptosis-inducing factor translocation to the nucleus was observed. Apoptosis resistance and PARP-1 hyperactivation were overcome by incubating the patient's cells with antioxidants. These results provide evidence for a novel form of AOA characterized by sensitivity to DNA damaging agents, oxidative stress, PARP-1 hyperactivation but resistance to apoptosis.

Item Type:	Refereed Article
Keywords:	ataxia oculomotor apraxia, cell death
Research Division:	Medical and Health Sciences
Research Group:	Neurosciences
Research Field:	Neurology and Neuromuscular Diseases
Objective Division:	Health
Objective Group:	Other Health
Objective Field:	Health not elsewhere classified
Author:	Gueven, N (Dr Nuri Guven)
ID Code:	79281
Year Published:	2007
Web of Science® Times Cited:	10
Deposited By:	Pharmacy
Deposited On:	2012-08-29
Last Modified:	2014-11-04
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