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

• DOI: 10.1371/journal.pgen.1002405
• Publication Date: 2011-12-08T21:51:50Z
• Authors: Dick Jaarsma; Ingrid van der Pl...; Monique C. de Waard; Elize D. Haasdijk; Renata Brandt; Marcel Vermeij; Yvonne Rijksen; Alex Maas; Harry van Steeg; Jan H. J. Hoeijma...; Gijsbertus T. J. ...
• Keywords: Cockayne syndrome

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