| Summary: | Huntington disease (HD) is a dominantly inherited neurodegenerative disease, which
is caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt).
Increasing evidence suggests that the N-methyl-D-aspartate (NMDA)-type glutamate
receptor plays a role in mediating death of striatal medium-sized spiny neurons
(MSNs) observed in HD. For example, previous results from our laboratory
demonstrate that NMDA receptor (NMDAR)-mediated current and toxicity is
increased in neurons from the Yeast Artificial Chromosome (YAC) transgenic mouse
model expressing huntingtin with 72 polyQ (YAC72), and suggest that an increase in
surface NMDAR number is the trigger for increased cytosolic calcium, ultimately
resulting in activation of caspases and leading to neuronal death. Here, I hypothesize
that potentiation of NMDAR surface expression and excitotoxicity by mutant htt (mhtt)
may be mediated in part by interaction with membrane-associated guanylate kinases
(MAGUKs) such as PSD-95 or SAP102. I report the novel finding that htt is
co-immunoprecipitated with SAP102 in HEK293T cells and in striatal tissue from
wild-type and YAC transgenic mice, but that the association of SAP102 with the
NMDAR NR2B subunit or htt is not altered by htt polyQ length. However, by using a
Tat-NR2B9c peptide to block binding between NR2B and either SAP 102 or PSD-95
in cultured striatal neurons, I show that this interaction plays a key role in mediating
the increase in NMDAR surface expression and NMDA-induced toxicity observed
with mhtt expression. Moreover, the Tat-NR2B9c peptide has no effect on glutamate
receptor 1 (GluRl) surface expression or staurosporine-induced toxicity. The mechanism by which SAP 102 and/or PSD-95 mediates the altered NMDAR trafficking and function observed with mhtt expression remains to be explored. My research may help to elucidate further the mechanisms underlying enhanced excitotoxicity in HD. === Medicine, Faculty of === Graduate
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