Oxidative DNA damage is implicated in brain aging, neurodegeneration and neurological diseases. Damage can be created by normal cellular metabolism, which accumulates with age, or by acute cellular stress conditions which create bursts of oxidative damage. Brain cells have a particularly high basal level of metabolic activity and use distinct oxidative damage repair mechanisms to remove oxidative damage from DNA and dNTP pools. Accumulation of this damage in the background of a functional DNA repair response is associated with normal aging, but defective repair in brain cells can contribute to neurological dysfunction. Emerging research strongly associates three common neurodegenerative conditions, Alzheimer’s, Parkinson’s and stroke, with defects in the ability to repair chronic or acute oxidative damage in neurons. This review explores the current knowledge of the role of oxidative damage repair in preserving brain function and highlights the emerging models and methods being used to advance our knowledge of the pathology of neurodegenerative disease.

Neurons are terminally differentiated cells with a high rate of metabolism and multiple biological properties distinct from their undifferentiated precursors. Previous studies showed that nucleotide excision DNA repair is down-regulated in post-mitotic muscle cells and neurons. Here, we characterize DNA damage susceptibility and base excision DNA repair (BER) capacity in undifferentiated and differentiated human neural cells. The results show that undifferentiated human SH-SY5Y neuroblastoma cells are less sensitive to oxidative damage than their differentiated counterparts, in part due to having robust BER capacity, which is heavily attenuated in the post-mitotic neurons. The reduction in BER activity in the differentiated cells correlates with diminished protein levels of key long patch BER components FEN-1, PCNA and Ligase I. Thus, due to their higher BER capacity, proliferative neural progenitor cells are more efficient at repairing DNA damage compared to their neuronally differentiated progeny.

Telomeres are critical for cell survival and functional integrity. Oxidative DNA damage induces telomeric instability and cellular senescence that are associated with normal aging and segmental premature aging disorders such as Werner Syndrome and Rothmund-Thompson Syndrome, caused by mutations in WRN and RECQL4 helicases respectively. Characterizing the metabolic roles of RECQL4 and WRN in telomere maintenance is crucial in understanding the pathogenesis of their associated disorders. We have previously shown that WRN and RECQL4 display a preference in vitro to unwind telomeric DNA substrates containing the oxidative lesion 8-oxoguanine. Here, we show that RECQL4 helicase has a preferential activity in vitro on telomeric substrates containing thymine glycol, a critical lesion that blocks DNA metabolism, and can be modestly stimulated further on a D-Loop structure by TRF2, a telomeric shelterin protein. Unlike that reported for telomeric D-Loops containing 8-oxoguanine, RECQL4 does not cooperate with WRN to unwind telomeric D-Loops with thymine glycol, suggesting RECQL4 helicase is selective for the type of oxidative lesion. RECQL4’s function at the telomere is not yet understood, and our findings suggest a novel role for RECQL4 in the repair of thymine glycol lesions to promote efficient telomeric maintenance.

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Striatal-specific activation of the kinase complex mTORC1 may improve pathological symptoms of Huntington’s disease.

Strategies using HDAC inhibitors—and overcoming resistance to them—may improve clinical outcome for some cancer patients.

Glioblastoma (GBM) is an aggressive brain cancer that is often characterized by a hypoxic microenvironment. Hypoxia-inducible factors (HIFs) transcriptionally promote multiple processes associated with GBM progression. Hu et al. found that hypoxia-induced HIF1α in GBM increased the production of a microRNA (miRNA) that drove the proliferation of glioma-initiating cells (GICs), a subpopulation of cells that may promote the growth and recurrence of GBM. The abundance of various miRNAs was increased by hypoxia, but only the functional blocking of miR-215 decreased the proliferation of cultured patient tumor–derived GICs in intracranial xenografts in mice. The amount of mature miR-215 and pre-miR-215, but not that of pri-miR-215, was increased in GICs cultured under hypoxic conditions, suggesting that the production of miR-215 was enhanced at a posttranscriptional step in the miRNA biogenesis pathway. However, the abundance of the Drosha and Dicer complexes that mediate this step was not increased by hypoxia. HIF1α, the abundance of which was increased in hypoxic GICs, interacted with the Drosha complex on pri-miR-215, and silencing HIF1α prevented the hypoxia-induced increase in the amount of miR-215 in GICs. Microarray and reporter analyses in GICs revealed that miR-215 targets and silences the mRNA encoding the histone demethylase KDM1B. Knocking down KDM1B in GICs increased neurosphere formation and the expression of genes associated with glucose metabolism in GIC cultures, and endothelial cells cultured in medium conditioned by KDM1B-deficient GICs exhibited increased migration. Decreased abundance of KDM1B in GBM patient tumors correlated with increased expression of HIF1A and miR-215 and with poor patient survival. The findings identify a miRNA biogenesis-targeted pathway through which hypoxia promotes GBM growth.J. Hu, T. Sun, H. Wang, Z. Chen, S. Wang, L. Yuan, T. Liu, H.-R. Li, P. Wang, Y. Feng, Q. Wang, R. E. McLendon, A. H. Friedman, S. T. Keir, D. D. Bigner, J. Rathmell, X.-d. Fu, Q.-J. Li, H. Wang, X.-F. Wang, MiR-215 is induced post-transcriptionally via HIF-Drosha complex and mediates glioma-initiating cell adaptation to hypoxia by targeting KDM1B. Cancer Cell 29, 49–60 (2016). [PubMed]