title: 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 Xpd(XPCS) 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.
authors.affiliation: Department of Neuroscience, Erasmus University Medical Center, Rotterdam, The Netherlands. d.jaarsma@erasmusmc.nl
authors.forename: Dick
authors.initials: D
authors.lastname: Jaarsma
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.forename: Elize D
authors.initials: ED
authors.lastname: Haasdijk
authors.forename: Renata
authors.initials: R
authors.lastname: Brandt
authors.forename: Marcel
authors.initials: M
authors.lastname: Vermeij
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Rijksen
authors.forename: Alex
authors.initials: A
authors.lastname: Maas
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D003057:Cockayne Syndrome / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D049914:DNA Repair-Deficiency Disorders; D004195:Disease Models, Animal; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics; D051379:Mice; D009186:Myelin Sheath / Q000235:genetics / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017354:Point Mutation; D014983:Xeroderma Pigmentosum / Q000235:genetics; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics* / Q000378:metabolism; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D051759:Xeroderma Pigmentosum Group D Protein; C497293:Ercc2 protein, mouse