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The role of accumulated DNA damage in cognitive decline: Potential mouse models for accelerated aging of the brain

Projectomschrijving

In dit onderzoek hebben we onderzocht in hoeverre DNA schade kan bijdragen aan cognitieve achteruitgang bij veroudering. We hebben daartoe een muismodel onderzocht (ERCC1) waarin de DNA schade sneller toeneemt, door een verminderd DNA herstel mechanisme. Muizen met zo'n mutatie verouderen sneller en leven korter. We hebben gevonden dat de hersenen van de jonge ERCC1 muizen geen pathologie hebben en goed functioneren. Bij wat oudere muizen is dit echter niet meer het geval. We concluderen hieruit dat DNA schade dus een belangrijke bijdrage kan leveren aan de cognitieve problemen die plaatsvinden bij veroudering.

Producten

Titel: DNA damage and ageing: new-age ideas for an age-old problem.
Auteur: Garinis GA, van der Horst GT, Vijg J, Hoeijmakers JH
Magazine: Nature Cell Biology
Titel: Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity.
Auteur: Garinis, G.A., Uittenboogaard, L.M., Stachelscheid, H., Fousteri, M., van Ijcken, W., Breit, T.M., van Steeg, H., Mullenders, L.H., van der Horst, G.T.J., Brüning, J.C., Niessen, C.M., Hoeijmakers, J.H.J., and Schumacher, B.
Magazine: Nature Cell Biology
Titel: Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice.
Auteur: de Waard MC, van der Pluijm I, Zuiderveen Borgesius N, Comley LH, Haasdijk ED, Rijksen Y, Ridwan Y, Zondag G, Hoeijmakers JH, Elgersma Y, Gillingwater TH, Jaarsma D.
Magazine: Acta Neuropathologica
Titel: An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair.
Auteur: Andressoo JO, Weeda G, de Wit J, Mitchell JR, Beems RB, van Steeg H, van der Horst GT, Hoeijmakers JH (2009)
Magazine: Molecular and Cellular Biology
Titel: Delayed and accelerated aging share common longevity assurance mechanisms. PLoS Genet
Auteur: Schumacher, B., van der Pluijm, I., Moorhouse, M.J., Kosteas, T., Robinson, A.R., Suh, Y., Breit, T.M., van Steeg, H., Niedernhofer, L.J., van Ijcken, W., Bartke, A., Spindler, S.R., Hoeijmakers, J.H., van der Horst, G.T.J. and Garinis, G.A
Magazine: PLoS Genetics
Titel: Delayed and accelerated aging share common longevity assurance mechanisms
Auteur: Schumacher B, van der Pluijm I, Moorhouse MJ, Kosteas T, Robinson AR, Suh Y, Breit TM, van Steeg H, Niedernhofer LJ, van Ijcken W, Bartke A, Spindler SR, Hoeijmakers JH, van der Horst GT, Garinis GA
Magazine: PLoS Biology
Titel: DNA damage and ageing: new-age ideas for an age-old problem.
Auteur: Garinis, G.A., van der Horst, G.T.J., Vijg, J., and Hoeijmakers, J.H.J.
Magazine: Nature Cell Biology
Titel: Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity
Auteur: Garinis GA, Uittenboogaard LM, Stachelscheid H, Fousteri M, van Ijcken W, Breit TM, van Steeg H, Mullenders LH, van der Horst GT, Brüning JC, Niessen CM, Hoeijmakers JH, Schumacher B.
Magazine: Nature Cell Biology
Titel: Molecular Mechanisms of Learning, Memory and Aging
Auteur: Nils Zuiderveen Borgesius

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Samenvatting van de aanvraag

Recent progress in aging research has provided a solid basis for the involvement of genome maintenance mechanisms as an anti aging factor. Using genetically defined mouse models with Nucleotide Excision Repair (NER) defects, we have obtained strong evidence that induction and accumulation of (oxidative) DNA damage is a major contributor to age-related diseases. In the current proposal, we will investigate the impact of accumulated DNA damage on cognitive function. The brain is a tissue with one of the highest levels of oxidative metabolism. As a consequence, neuronal DNA is bombarded by oxygen radicals, which results in more than ten thousands hits per day for a single neuron. Since a neuron has to function for an entire lifetime, it is critically dependent on efficient cellular DNA-repair pathways to fix the damage. Nevertheless, for reasons that are still poorly understood, oxidative DNA damage increases at older age, as does the mutation frequency. Moreover, DNA damage is increased in neurodegenerative diseases like Alzheimer's disease. This damage is likely to affect neuronal function and may directly contribute to cognitive decline. Yet, it is hitherto unknown to which extend accumulated DNA damage directly contributes to cognitive decline. Several studies have shown that reducing oxidative damage by dietary restriction is effective in both increasing the age of animals as well as in delaying their cognitive decline. However, these effects may also be attributed to decreased protein and/or lipid peroxidation. Thus, we are currently unable to dissect the role of oxidative DNA damage in cognitive decline. Using mouse models with a diminished DNA repair system, we are able to specifically look at impact of accumulated (oxidative) DNA damage on neuronal aging. These mice show several symptoms that are associated with aging including a shortened lifespan. In the current proposal, we aim to employ these mutants to the investigate the following questions: (1) The impact of oxidative DNA damage on neuronal plasticity and cognitive function. (2) The effect of increased DNA damage on neurodegenerative diseases. (3) The effect of anti-oxidant drugs on cognitive decline caused by accumulated DNA damage. (4) The effect of accumulated neuronal DNA damage on the onset of age-related pathology in peripheral tissues. We propose to use nucleotide excision repair (NER) mutants with a lifespan of approximately 6 months. In addition we propose to use conditional NER mutants. This allows us to accelerate the accumulation of damaged DNA in distinct areas of the brain. We are in particular interested in a comparison between the hippocampus and the cerebellum, since they show marked differences upon aging. Moreover, we can use these conditional mutants to discriminate between the impacts of neuronal versus glial 'aging'. In addition, we can test to what extend the brain functions as a master regulator of aging. We will do this by deleting the NER genes in distinct brain areas and by studying its effect on the age-related decline of peripheral tissues. If DNA damage proofs to be an important factor in cognitive decline, these mice will be valuable to serve as mouse-models for accelerated aging of the brain. These mice can then be used to find drugs that are able to delay the aging process. We will use a multidisciplinary approach to study the aforementioned questions at the molecular, cellular and systems level. This is a collaborative grant proposal, which brings together the unique expertise of the Department of Genetics on DNA repair and its relation to aging, and the expertise of the Department of Neuroscience on hippocampal and cerebellar function.

Onderwerpen

Kenmerken

Projectnummer:
91206113
Looptijd: 100%
Looptijd: 100 %
2006
2010
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. Y. Elgersma
Verantwoordelijke organisatie:
Erasmus MC