Accelerated Age-Related Cognitive Decline and Neurodegeneration, Caused by Deficient DNA Repair

Borgesius, Nils Z.; Waard, Monique C. de; Pluijm, Ingrid van der; Omrani, Azar; Zondag, Gerben; Horst, Gijsbertus T. J. van der; Melton, David W.; Hoeijmakers, Jan H.J.; Jaarsma, Dick; Elgersma, Ype

doi:10.1523/jneurosci.1589-11.2011

Cited by 109 publications

(110 citation statements)

References 82 publications

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“…The upregulation of these classes of proteins marks an increased recruitment of astrocytes and/or other glial cells indicating an increase in neuronal damage and inflammation in the cerebellum of KO mice. This is in line with previous studies that have shown that aging and the lack of efficient DNA repair can trigger neurodegenerative and inflammatory processes (23,(25)(26)(27). Other proteins found to be up-regulated are extracellular proteins that are known to interact with or modify the extracellular environment (HTRA1 and Lama2) as well as cell adhesion molecules (PECAM-1 and MCAM).…”

Section: Resultssupporting

confidence: 91%

Spatio-temporal Analysis of Molecular Determinants of Neuronal Degeneration in the Aging Mouse Cerebellum

Graaf

Vermeij

Waard

et al. 2013

Molecular & Cellular Proteomics

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The accumulation of cellular damage, including DNA damage, is hypothesized to contribute to aging-related neurodegenerative changes. DNA excision repair crosscomplementing group 1 (Ercc1) knock-out mice represent an accepted model of neuronal aging, showing gradual neurodegenerative changes, including loss of synaptic contacts and cell body shrinkage. Here, we used the Purkinje cell-specific Ercc1 DNA-repair knockout mouse model to study aging in the mouse cerebellum. We performed an in-depth quantitative proteomics analysis, using stable isotope dimethyl labeling, to decipher changes in protein expression between the early (8 weeks), intermediate (16 weeks), and late (26 weeks) stages of the phenotypically aging Ercc1 knock-out and healthy littermate control mice. The expression of over 5,200 proteins from the cerebellum was compared quantitatively, whereby 79 proteins (i.e. 1.5%) were found to be substantially regulated during aging. Nearly all of these molecular markers of the early aging onset belonged to a strongly interconnected network involved in excitatory synaptic signaling. Using immunohistological staining, we obtained temporal and spatial profiles of these markers confirming not only the proteomics data but in addition revealed how the change in protein expression correlates to synaptic changes in the cerebellum. In summary, this study provides a highly comprehensive spatial and temporal view of the dynamic changes in the cerebellum and Purkinje cell signaling in particular, indicating that synapse signaling is one of the first processes to be affected in this premature aging model, leading to neuron morphological changes, neuron degeneration, inflammation, and ultimately behavior A link between DNA damage and the process of aging has been firmly established (1, 2). The brain in particular is a vulnerable organ that is plagued by various neurodegenerative disorders that have been related to aging, i.e. Alzheimer and Parkinson disease. The study of the early onset of agerelated neurodegenerative diseases is challenging, because there are not many confident early molecular determinants that predict their development. Therefore, progeroid syndromes (showing premature aging) are often used as a model for segmental aging as they show consistent and predictive elements of the aging phenotype (e.g. cessation of growth and development, hearing loss, and severe and progressive neuron dysfunction) (1, 3). These accelerated aging syndromes have in common that they carry defects in one or multiple proteins involved in DNA damage repair mechanisms.A well established progeroid mouse model is the excision repair cross-complementing group 1 (Ercc1) 1 gene knock-out (4, 5). The Ercc1-xeroderma pigmentosum group F complex acts as a nuclease in the nucleotide excision repair pathway and has an important function in both global genome and transcription-coupled DNA damage repair. Besides its role in nucleotide excision repair, Ercc1 is also involved in interstrand cross-link repair and oxidative damage repair. The accum...

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Section: Resultssupporting

confidence: 91%

Spatio-temporal Analysis of Molecular Determinants of Neuronal Degeneration in the Aging Mouse Cerebellum

Graaf

Vermeij

Waard

et al. 2013

Molecular & Cellular Proteomics

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“…Similarly, following Cre expression in Purkinje cells, Xpa c/À /Csb m/m mice showed asynchronous loss of Purkinje neurons. Such an asynchronous neuronal degeneration is consistent with cell death resulting from the accumulation of stochastic DNA damage, and strongly resembles the pattern of neuronal degeneration in forebrain and cerebellum specific ERCC1-deficient mice (Borgesius et al, 2011;de Graaf et al, 2013).…”

Section: Neuron-specific Inactivation Of Xpa Triggers Progressive Neusupporting

confidence: 67%

“…Mechanistic overlap is also suggested by overlapping gene expression profiles (Schumacher et al, 2008). Furthermore, neurodegenerative features of our neuron-specific Xpa-deficient Csb m/m mice strongly resemble the neurodegenerative features of mice with neuron-specific deletion of Ercc1 (Borgesius et al, 2011). A potential lesson from Ercc1-deficient mice for the interpretation of the short life span exhibited by Csb m/m /Xpa À/À and Xpg À/À mutant mice, is that restoring Ercc1 expression specifically in the liver via intercrossing with a liver-specific Ercc1 transgenic mouse line, results in considerable reduction of weight loss and a prolonged life span (Selfridge et al, 2001).…”

Section: Severe Short-living Phenotypes In Xpf/ercc1-deficient Micesupporting

confidence: 55%

“…In mouse models for neurodegenerative diseases such as mutant SOD1 amyotrophic lateral sclerosis mice, the appearance of activated microglia correlates with the onset of neuronal and axonal degeneration (Hossaini et al, 2011;Jaarsma et al, 2008;Perry et al, 2010). Also in ubiquitous and neuron-specific Ercc1-deficient mice that are impaired in NER as well interstrand crosslink repair, and double strand break repair, and that develop a progressive neurodegenerative phenotype, the appearance of activated microglia correlates with the onset of neuronal and axonal degeneration (Borgesius et al, 2011;de Waard et al, 2010). However, we found no clear evidence for such neurodegenerative changes in Csb m/m mice.…”

Section: Chronic Microglia Cell Activation In Myelin-rich Areas Inmentioning

confidence: 99%

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Cockayne syndrome pathogenesis: Lessons from mouse models

Jaarsma

Pluijm

Horst

et al. 2013

Mechanisms of Ageing and Development

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“…Global Ercc1 mutants as well as neuron-specific Ercc1 mutants exhibit an age-dependent decrease in neuronal plasticity, and progressive neuronal pathology, suggestive of neurodegenerative processes [24]. These mice do not show frank AD pathology (Keene et.…”

mentioning

confidence: 99%

Modeling Alzheimer’s disease in progeria mice. An age-related concept

Sharma

Darvas

Keene

et al. 2018

Pathobiology of Aging & Age-related Diseases

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The prevalence of Alzheimer’s disease (AD) is expected to dramatically increase in older people worldwide. Efforts to find disease-modifying treatments have been largely unsuccessful because of the focus on disease-specific pathogenesis, and lack of animal models to study AD in the context of aging and age-related co-morbidities. The geroscience approach to studying AD would suggest that modulation of aging per se would be a useful strategy, but a mammalian model system that combines both aging and AD is not available. One approach to study old age and AD is to utilize murine models of progeroid syndrome, which can provide a number of advantages not only for basic aging biology but also for preclinical drug testing. A progeria background, such as the Ercc1 mutant mouse (Ercc1−/Δ), provides an aging component not seen in current murine models of AD that lack age-related co-morbidities typical of AD patients.Ercc1−/Δ mice experience the same types of stochastic endogenous DNA damage as WT mice, but accumulate lesions faster due to impaired DNA repair, which accelerates the normal aging process by 6-fold. These mice do not show frank AD pathology but represent a predisposed or hypersensitive environment for AD pathology, where pathogenic elements of AD can be introduced, either by crossing with well-established AD transgenic mouse lines, or transcranial stereotaxic delivery directly into the brain. Since Ercc1−/Δ mice age five to six times faster than WT mice, very rapid characterization and testing of therapeutic interventions is possible. Studies are urgently needed to capitalize on the highly informative potential of this novel AD mouse model.

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Accelerated Age-Related Cognitive Decline and Neurodegeneration, Caused by Deficient DNA Repair

Cited by 109 publications

References 82 publications

Spatio-temporal Analysis of Molecular Determinants of Neuronal Degeneration in the Aging Mouse Cerebellum

Spatio-temporal Analysis of Molecular Determinants of Neuronal Degeneration in the Aging Mouse Cerebellum

Cockayne syndrome pathogenesis: Lessons from mouse models

Modeling Alzheimer’s disease in progeria mice. An age-related concept

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