THE ROLE OF Cdk5 IN THE DNA DAMAGE RESPONCE DURING AGING AND NEURODEGENERATION

Harvard Medical School, Boston MA

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Abstract

Alzheimer's disease (AD) is the leading cause for dementia that afflicts more than 4.5 million people in[unreadable] this country. Various genetic and epigenetic factors are implicated in the etiology of AD, among which aging[unreadable] is the single most significant factor.[unreadable] Cyclin dependent kinase 5 (Cdk5) is a small protein Ser/Thr kinase. When associated with its regulatory[unreadable] activator p35 or p39, Cdk5 plays an essential role in neuronal positioning, axon guidance, and synaptic[unreadable] plasticity. Under neurotoxic conditions, p35 is cleaved by calpain to become p25, which encompasses the[unreadable] carboxyl-terminal two thirds of p35. p25 is more stable and displays an altered subcellular localization from[unreadable] p35. These properties of p25 cause aberrant activation of Cdk5. We created an inducible p25 transgenic[unreadable] mouse model (CK-p25) that manifests profound neurodegeneration, neurofibrillary tangle pathology, and[unreadable] elevated Abeta peptides in the cortex and hippocampus. These observations indicate that elevation of p25[unreadable] alone can cause AD-like pathology.[unreadable] Recently, we examined the transcriptional profile of the CK-p25 mice by microarray analyses.[unreadable] Remarkably, a total of 82 genes known to be involved in DNA repair/replication and/or cell cycle progression[unreadable] are dramatically upregulated in 2-week induced CK-p25 mice. Genes include a number of well known DNA[unreadable] damage response genes such as Rad51, nuclear protein 95, and uracil DNA glycosylase, some of which[unreadable] were upregulated over 30-fold (Affymetrix expression values). Such an expression profile strongly suggests[unreadable] DNA damage-induced responses as an early and possibly causative event in p25-mediated[unreadable] neurodegeneration. p25 may cause DNA damage, and/or play an apical role in the DNA damage response.[unreadable] The NAD+-dependent deacetylase SIRT1, shown to be an important modulator of lifespan in many[unreadable] different organisms from yeast to mammals, is upregulated in postmortem AD brain samples and in CK-p25[unreadable] Tg brains. In addition, in collaboration with Dr. David Sinclair, we found that SIRT1 overexpression or[unreadable] activation by resrevatrol resulted in protection against neurotoxicity in p25 expressing neurons. SIRT1 has[unreadable] been shown to modify chromatin and its yeast homologue, Sir2, functions to maintain genomic stability.[unreadable] Thus, it is possible that SIRT1 represses p25-mediated DNA damage and that this activity accounts for the[unreadable] neuroprotective activity of SIRT1.[unreadable] We will collaborate with Drs. Bruce Yankner, David Sinclair, and Junying Yuan to test the hypothesis that[unreadable] DNA damage response elicited by the p25/Cdk5 kinase plays an important role in neurodegeneration. We[unreadable] will also determine the role of SIRT1 in ameliorating neurodegeneration and the DNA damage response[unreadable] induced by p25.