title: Synaptic proteome changes in a DNA repair deficient ercc1 mouse model of accelerated aging.
abstract: Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used Ercc1 mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged Ercc1 mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and Ercc1 mutant hippocampal neurons displayed normal outgrowth and synapse formation in vitro. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline.
authors.affiliation: Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam,  VU University , De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Marlene J
authors.initials: MJ
authors.lastname: Végh
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
authors.forename: Yanto
authors.initials: Y
authors.lastname: Ridwan
authors.forename: Marion J M
authors.initials: MJ
authors.lastname: Sassen
authors.forename: Pim
authors.initials: P
authors.lastname: van Nierop
authors.forename: Roel C
authors.initials: RC
authors.lastname: van der Schors
authors.forename: Ka Wan
authors.initials: KW
authors.lastname: Li
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Ronald E
authors.initials: RE
authors.lastname: van Kesteren
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009419:Nerve Tissue Proteins; D020543:Proteome; D004720:Endonucleases; C499360:Ercc1 protein, mouse