Leon, Rebecca

Taurine, an endogenous ammo acid and neuromodulator, has been found to be
neuroprotective against numerous forms of neurotoxicity including glutamate-induced
excitotoxicity. Previously we have shown that taurine inhibits glutamate-induced
calcium influx through VGCCs and NMDA receptors. Although the neuroprotective
effects of taurine against excitotoxicity have been attributed to its intracellular Ca2+
regulatory functions, the complete mechanism underling taurine neuroprotection has
remained unclear. Using primary rat cortical neuronal cell cultures, we have determined
key cytosolic components to the mechanism of taurine neuroprotection. In this study we
have found that taurine inhibits excitotoxicity by suppressing glutamate-induced
elevations in [Ca2+]i, preventing calpain activation, and inhibiting reductions in Bel-
2:Bax ratios and consequently activation of the intrinsic pathway.

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.