Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology

Abstract

Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.

Effects of organic and inorganic mercury(II) on gene expression via DNA conformational changes

“…Transcriptional repression has been reported to induce atypical neuronal cell death that is distinct from apoptosis, necrosis, or autophagy (Hoshino et al, 2006). In addition to protein expression via mRNA synthesis, transcription contributes gene regulation via non-coding RNAs (Tal and Tanguay, 2012) and genomic stability via transcription-coupled DNA repair (Jaarsma et al, 2011). Together with our present study, these results suggest that aberrant transcription of Hg-bound DNA underlies the neurotoxic mechanisms of Hg.…”

Mammalian Transcription-Coupled Excision Repair

“…These mice recapitulate some of the CS clinical features Jaarsma et al 2011), but the features are much less pronounced than in man. This milder phenotype has been attributed to the shorter lifespan of mice ( 2.5 years), possibly too short to acquire sufficient damage for significant effects.…”

Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span

“…Systemic loss or mutation of several factors required for telomeric stability, response to replication stress, or nucleotide excision repair (NER) cause phenotypes that resemble premature aging in mice (44,(53)(54)(55)(56)(57)(58)(59)(60) and segmental progeria syndromes in humans, including XPF/ERCC1 in xeroderma pigmentosum, ERCC6/8 in Cockayne syndrome, and ATR in Seckel syndrome (61).…”