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Signaling pathways involved in enhanced NMDA receptor-dependent excitotoxicity in a mouse model of Huntington disease Fan, Jing


Huntington disease (HD) is an inherited neurodegenerative disease lacking effective treatment, characterized by involuntary movements, psychiatric disorders, and cognitive symptoms. Pathology shows prominent degeneration of γ-aminobutyric acid (GABA)-ergic medium-sized spiny neurons (MSNs) of the striatum and certain cortical layers (Vonsattel and DiFiglia, 1998). HD is caused by a dominant mutation in the HD gene that leads to >35 glutamine repeats (polyQ) near the N-terminus of the protein huntingtin (htt) (The Huntington’s Disease Collaborative Research Group, 1993). Increasing evidence suggests that the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR) plays a role in mediating death of MSNs observed in HD (Fan and Raymond, 2007). Previous results from our laboratory demonstrate that NMDAR-mediated current and toxicity are increased in MSNs from the Yeast Artificial Chromosome (YAC) transgenic mouse model expressing polyglutamine-expanded full-length human htt (Shehadeh et al., 2006; Zeron et al., 2002). However, the mechanism underlying altered function and enhanced toxicity of NMDAR in HD remains unknown. Previous studies have shown that membrane-associated guanylate kinases (MAGUKs), such as postsynaptic density protein 95 (PSD-95) modulate NMDAR surface expression and excitotoxicity in rat hippocampal and cortical neurons (Aarts et al., 2002; Roche et al., 2001), and that htt interacts with PSD-95 in a polyglutamine dependent manner (Sun et al., 2001). Here, I tested the hypothesis that an altered association and/or regulation between PSD-95 and NMDARs in mutant htt-expressing cells contributes to increased susceptibility to excitotoxicity and investigated mechanism by which this occurs. Specifically, I investigated the association of PSD-95 with htt and the NMDAR GluN2 subunits; signaling downstream of activation of the NMDAR/PSD-95 complex; and NMDA-induced cell death. My results suggest that at the presymptomatic stage of HD, the enhanced interaction of PSD-95 with GluN2B, and its signaling through p38 mitogen-activated protein kinase (MAPK) but not neuronal nitric oxide synthase (nNOS) activation, contributes to mutant htt-mediated sensitivity to NMDAR-dependent excitotoxicity in YAC128 striatal neurons. This work contributes to the understanding of both NMDAR-dependent neuronal death mechanisms in striatal neurons and early synaptic changes in HD pathogenesis, as well as providing potential drug candidates for future HD treatment.

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