Degeneration

Huntington's Disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the Huntingtin gene IT15. In this study we demonstrated that Bcl-2 interacting mediator of cell death Extra Long (BimEL) protein expression was significantly increased in cells expressing mutant Huntingtin (mHtt). Moreover, striatal BimEL expression remained high in an R6/2 HD mouse model throughout the disease progression. Utilizing novel BimEL phospho-mutants we demonstrated the phosphorylation of Ser65 to be important for the stabilization of BimEL. We provided evidence that impaired proteasome function, increased JNK activity and reduced striatal BDNF lead to changes in the phosphorylation of BimEL, thereby promoting its stabilization specifically within the striatum of R6/2 mice. Furthermore, knocking down BimEL expression prevented mHtt-induced cell death in a HD cell culture. Taken together, these findings suggest that BimEL may contribute to the selective neurodegeneration and pathogenesis of HD.

Alzheimer's disease (AD) is an increasingly common neurological disorder that mainly affects memory formation and retention. It is characterized by unique intercellular neurofibrillary tangles and extracellular beta-amyloid plaques. Histone deacetylase inhibitors (HDACi's) are competitive antagonists against histone deacetylases, causing histone acetyltransferases to acetylate the genome unregulated. This thesis investigates the use of new histone deacetylase inhibitors on recovering memory in a mouse model of Alzheimer's disease. By use of a fear conditioning paradigm, we have shown that these HDACI's increase memory in AD mice, but show either no effect or a positive effect in wild-type mice. Future experiments will investigate the efficacy of compound 966 and the spine density of hippocampal brain slices after fear conditioning trials.