Synaptic Proteome Changes in a DNA Repair Deficient <i>Ercc1</i> Mouse Model of Accelerated Aging

Végh, Marlene J.; Waard, Monique C. de; Pluijm, Ingrid van der; Ridwan, Yanto; Sassen, Marion J M; Nierop, Pim van; Schors, Roel C. van der; Li, Ka Wan; Hoeijmakers, Jan H.J.; Smit, August B.; Kesteren, Ronald E. van

doi:10.1021/pr201203m

Cited by 31 publications

(26 citation statements)

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“…Immunoblotting was performed following a standard protocol [24]. In short, the samples were heated for 5 min at 95°C in a Laemmli sample buffer, and 7 μg of protein was loaded on a TGX stain-free gradient gel (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

Individual and Familial Susceptibility to MPTP in a Common Marmoset Model for Parkinson's Disease

et al. 2016

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Introduction: Insight into susceptibility mechanisms underlying Parkinson's disease (PD) would aid the understanding of disease etiology, enable target finding and benefit the development of more refined disease-modifying strategies. Methods: We used intermittent low-dose MPTP (0.5 mg/kg/week) injections in marmosets and measured multiple behavioral and neurochemical parameters. Genetically diverse monkeys from different breeding families were selected to investigate inter- and intrafamily differences in susceptibility to MPTP treatment. Results: We show that such differences exist in clinical signs, in particular nonmotor PD-related behaviors, and that they are accompanied by differences in neurotransmitter levels. In line with the contribution of a genetic component, different susceptibility phenotypes could be traced back through genealogy to individuals of the different families. Conclusion: Our findings show that low-dose MPTP treatment in marmosets represents a clinically relevant PD model, with a window of opportunity to examine the onset of the disease, allowing the detection of individual variability in disease susceptibility, which may be of relevance for the diagnosis and treatment of PD in humans.

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Section: Methodsmentioning

confidence: 99%

Individual and Familial Susceptibility to MPTP in a Common Marmoset Model for Parkinson's Disease

et al. 2016

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“…Whichever is the case, ROS-related changes to biomolecules are important in the pathogenesis of many serious chronic diseases including ocular disorders such as cataract, glaucoma and age-related macular degeneration (AMD) [3]. In this respect, AMD seems to be of special interest, since aging is a primary factor in its etiology, and oxidative DNA damage may be involved in premature aging [4]. Degenerative changes in retinal pigment epithelium (RPE)—a monolayer of cells between the neural retina and the retinal basement membrane (Bruch’s membrane), resulting from age-related and oxidative stress-induced damage (in RPE cells)—are an anatomical hallmark of AMD [5].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial and Nuclear DNA Damage and Repair in Age-Related Macular Degeneration

Błasiak

Głowacki

Kauppinen

et al. 2013

IJMS

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Aging and oxidative stress seem to be the most important factors in the pathogenesis of age-related macular degeneration (AMD), a condition affecting many elderly people in the developed world. However, aging is associated with the accumulation of oxidative damage in many biomolecules, including DNA. Furthermore, mitochondria may be especially important in this process because the reactive oxygen species produced in their electron transport chain can damage cellular components. Therefore, the cellular response to DNA damage, expressed mainly through DNA repair, may play an important role in AMD etiology. In several studies the increase in mitochondrial DNA (mtDNA) damage and mutations, and the decrease in the efficacy of DNA repair have been correlated with the occurrence and the stage of AMD. It has also been shown that mitochondrial DNA accumulates more DNA lesions than nuclear DNA in AMD. However, the DNA damage response in mitochondria is executed by nucleus-encoded proteins, and thus mutagenesis in nuclear DNA (nDNA) may affect the ability to respond to mutagenesis in its mitochondrial counterpart. We reported that lymphocytes from AMD patients displayed a higher amount of total endogenous basal and oxidative DNA damage, exhibited a higher sensitivity to hydrogen peroxide and UV radiation, and repaired the lesions induced by these factors less effectively than did cells from control individuals. We postulate that poor efficacy of DNA repair (i.e., is impaired above average for a particular age) when combined with the enhanced sensitivity of retinal pigment epithelium cells to environmental stress factors, contributes to the pathogenesis of AMD. Collectively, these data suggest that the cellular response to both mitochondrial and nuclear DNA damage may play an important role in AMD pathogenesis.

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“…The accumulation of DNA damage following Ercc1 gene inactivation results in the progeroid phenotype (2, 6). Recently, it was shown that global and neuron-specific Ercc1 mutant mice showed age-related neuronal changes in the spinal cord and the hippocampus (7,8). Here, we set out to monitor molecular changes in the cerebellum of Purkinje cell-specific Ercc1 knock-out mice by quantitative proteomics.…”

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confidence: 99%

“…Until now, most neuroproteomics studies have been directed at general protein composition of the synapse, with the emphasis on the synaptosomes (9), synaptic membranes (10,11), or post-and pre-synaptic densities (8,12) by using subcellular fractionation strategies on the whole brain or subcompartments. Here, we compared quantitatively the proteome from intact cerebella from Purkinje neuron-specific DNA-repair KO mice with cerebella from control mice at the age of 8, 16, and 26 weeks to monitor aging-related molecular changes in the cerebellum over time.…”

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confidence: 99%

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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Synaptic Proteome Changes in a DNA Repair Deficient Ercc1 Mouse Model of Accelerated Aging

Cited by 31 publications

References 65 publications

Individual and Familial Susceptibility to MPTP in a Common Marmoset Model for Parkinson's Disease

Individual and Familial Susceptibility to MPTP in a Common Marmoset Model for Parkinson's Disease

Mitochondrial and Nuclear DNA Damage and Repair in Age-Related Macular Degeneration

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

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