DNA repair dysfunction in neurodegeneration

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

We have studied DNA repair in individual primary rat neurons. These neurons repair many kinds of DNA damage, and it is particularly novel that they repair UV induced DNA damage. This is important because UV damage to DNA is removed by the DNA repair process called nucleotide excision repair, which is generally thought to be deficient in the CNS. We also find attenuation of oxidative DNA damage repair in differentiating neurons and we find that the DNA repair in the synaptic region is quite robust after oxidative stress. Furthermore, there seems to be a connection between neurotransmission and DNA repair because the addition of neurotransmitters to neurons increases DNA damage and repair. Specifically, we observed that non-toxic physiological levels of glutamate induced DNA damage and this damage was dependent upon calcium and mitochondrial ROS because calcium chelators and mitochondrial inhibitors prevented the DNA damage. We further showed that the glutamate-induced DNA damage induced APE1 mRNA and that APE1 is a key player in the repair of glutamate-induced DNA damage. The APE1 induction was shown to be dependent on signaling through a calcium and CREB-mediated pathway. Given that glutamate is the most abundant neurotransmitter, this raises the notion that there exists a connection between DNA damage, repair, memory and learning. There are numerous documented cases of neurodegeneration associated with genetic DNA repair defects. More recently mouse models have focused our attention on the correlation between neurodegeneration and mitochondrial DNA repair maintenance and repair. With this focus in mind, we have investigated the cellular localization and brain distribution patterns for Aprataxin (APTX), the protein deficient in ataxia with oculomotor apraxia (AOA1). APTX, together with TDP1, constitute a class of DNA repair enzymes that modify DNA ends prior to ligation. We were the first to report that an isoform of APTX is localized to mitochondria and that this isoform is expression in the cerebellum. Additionally, we showed that acute depletion of APTX in human cells caused mitochondrial dysfunction. Our results support the proposal that altered mitochondrial DNA repair may contribute, in part, to neurodegeneration see in AOA1 patients.