title: Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair.
abstract: Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage of Ercc1(Δ/-) mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an age-dependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases.
authors: Department of Neuroscience, Erasmus MC, 3015 GE, Rotterdam, The Netherlands, Cancer Genomics Center, Department of Genetics, Center for Biomedical Genetics, Erasmus MC, 3015 GE, Rotterdam, The Netherlands.
authors: Nils Z
authors: NZ
authors: Borgesius
authors: Monique C
authors: MC
authors: de Waard
authors: Ingrid
authors: I
authors: van der Pluijm
authors: Azar
authors: A
authors: Omrani
authors: Gerben C M
authors: GC
authors: Zondag
authors: Gijsbertus T J
authors: GT
authors: van der Horst
authors: David W
authors: DW
authors: Melton
authors: Jan H J
authors: JH
authors: Hoeijmakers
authors: Dick
authors: D
authors: Jaarsma
authors: Ype
authors: Y
authors: Elgersma
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000367:Age Factors; D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D049914:DNA Repair-Deficiency Disorders / Q000150:complications* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004720:Endonucleases / Q000172:deficiency; D005239:Fear / Q000523:psychology; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D016159:Tumor Suppressor Protein p53; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D053148:Caspase 3