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

• Main Author: Fan, Jing
• Language: English
• Published: University of British Columbia 2011
• Online Access: http://hdl.handle.net/2429/38094

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. === Medicine, Faculty of === Graduate