Grant: Doctoral Research Award - Priority Announcement: Huntington Disease

The NMDA receptor (NMDAR) is a key receptor in the brain for excitatory neurotransmission. Over-excitation of NMDARs leads to excitotoxicity, which has shown to have a role in the pathogenesis of several neurological diseases such as stroke, ALS and Huntington's Disease. Directly blocking NMDARs with antagonists has shown to be an ineffective clinical therapeutic for NMDAR-mediated excitotoxic diseases, likely due to the critical role of NMDARs in normal brain function. Instead, it may be possible to target signaling pathways downstream of NMDAR activation by modulating cellular activity related to cell death specifically, while leaving cell survival NMDAR function intact. Recent studies in our lab have indicated that nuclear translocation of Phosphatase and Tensin Homolog deleted on chromosome ten (PTEN), a tumor suppressor, has a key role in NMDAR-mediated excitotoxic neuronal death. To target this, we have designed the Tat-K13 interference peptide and have shown that Tat-K13 can block PTEN nuclear translocation and prevent neuron damage after NMDA excitotoxicity. Preliminary studies in our lab have supported the hypothesis that PTEN nuclear translocation may have a role in NMDAR-mediated excitotoxic neuron death in Huntington's Disease (HD). Using biochemistry, I have shown that PTEN nuclear translocation is significantly increased in neurons from HD transgenic mice after NMDA treatment. Similarly, blocking PTEN nuclear translocation using Tat-K13 significantly reduces NMDAR-mediated excitotoxic death in cultured striatal, cortical and hippocampal neurons from HD transgenic mice. These results strongly support my hypothesis. My current study will address my hypothesis by 1) determining the neuroprotective effects of Tat-K13 in HD, both in cultured cells and live HD transgenic mice and 2) characterizing the mechanism of PTEN nuclear translocation leading to neuron death. This study may be an important step towards developing new therapeutics for HD.