AUTOPHAGY, DNA DAMAGE AND ONSET OF HUNTINGTON'S DISEASE.

Harvard Medical School, Boston MA

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Linked publications & trials

Abstract

The goal of this proposal is to test the hypothesis that the reduction of key autophagy gene expression and[unreadable] autophagy function as a result of DNA damage during the aging process plays a key role in mediating the[unreadable] onset of Huntington's disease (HD). Mouse, Drosophila and C. elegans models of HD suggest that the[unreadable] cytotoxicity of expanded polyglutamine is highly dependent upon protein context and protein expression[unreadable] levels of mutant Htt. Autophagy plays an important role in regulating the intracellular accumulation of mutant[unreadable] Htt with expanded polyQ. The expression of beclin 1, a key gene involved in autophagy, decreased in an[unreadable] age-dependent fashion in human brains. Since beclin 1 gene is haploid insufficient in regulating[unreadable] autophagosome function, age-dependent decrease of beclin 1 expression may lead to a reduction of[unreadable] autophagic activity during aging. The hypothesis is that reduction of autophagy function in aging results in[unreadable] both increased oxidative stress induced DNA damage and reduced long-lived protein turnover which[unreadable] promotes the accumulation of mutant Htt. Increased accumulation of mutant Htt and oxidative stress may[unreadable] play an important role in promoting the onset of HD. This hypothesis will be tested in the following specific[unreadable] aims. Specific Aim 1 is to test,the hypothesis that the reduction of beclin 1 expression in aging human brains[unreadable] contributes to the onset of HD by generating beclin 1+/-; HdhQ111 mice and examining if 50% reduction of[unreadable] beclin 1 expression led to an increased accumulation of mutant Htt as well as to determine the[unreadable] consequence of autophagy deficiency on neuronal survival and functions. Specific Aim 2 is to examine the[unreadable] mechanism which led to the age-dependent reduction of beclin 1 expression by testing if the promoter of[unreadable] beclin 1 is preferentially damaged in aging human brains and particularly susceptible to oxidative damage in[unreadable] cellular models. The contribution of reduced expression of transcriptional factors regulating beclin 1[unreadable] expression will also be considered. Specific Aim 3 is to test the hypothesis that the reduction of autophagy[unreadable] function exacerbates the DNA damage during aging by increasing the accumulation of damaged[unreadable] mitochondria which further promotes the levels of intracellular ROS by examining aging beclin 1+/- mice and[unreadable] autophagy deficient cells for evidence of increased damaged mitochondria. Specific Aim 4 is to investigate[unreadable] the functional role of autophagy to oxidative DNA damage using CK-p25 mice as a model and to examine[unreadable] the roles of of DNA damage and autophagy deficiency to the accumulation of mutant Htt in HdhQ111; CKp25[unreadable] mice. The ability of SIRT1 activating molecules (STACs) to restore the autophagy function in CK-p25[unreadable] mice and to delay the onset of motor dysfunction in HD models will be determined. Understanding the[unreadable] mechanism by which DNA damage negatively regulates autophagy during aging would allow us to develop[unreadable] strategies to maintain normal autophagy function during aging process which may delay or prevent the onset[unreadable] of HD and other aging related neurodegenerative diseases.