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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Mutant huntingtin enhances excitotoxic cell death
M M Zeron1, N Chen, A Moshaver
1Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Molecular and Cellular Neurosciences
|February 13, 2001
Summary
Huntington's disease involves excitotoxicity from overactive NMDA-type glutamate receptors (NMDARs). Mutant huntingtin protein amplifies NMDAR-mediated excitotoxicity, particularly via NR1A/NR2B subtypes, contributing to neuron death.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) is linked to excitotoxicity in medium-sized spiny striatal neurons.
- Overactivation of NMDA-type glutamate receptors (NMDARs) is implicated in this neurodegeneration.
Purpose of the Study:
- To investigate if mutant huntingtin protein with a polyglutamine expansion exacerbates NMDAR-mediated excitotoxicity.
- To determine the role of specific NMDAR subtypes in this process.
Main Methods:
- HEK293 cells were coexpressed with mutant huntingtin (htt-138Q) and different NMDAR subtypes (NR1A/NR2A or NR1A/NR2B).
- Cells were exposed to NMDA, and excitotoxic cell death was quantified.
- Apoptotic features were assessed in agonist-dependent cell death.
Main Results:
- Coexpression of htt-138Q with NMDARs significantly increased excitotoxic cell death compared to controls.
- This effect was more pronounced with the NR1A/NR2B NMDAR subtype.
- Apoptotic cell death was observed with htt-138Q and NR1A/NR2B, but not with NR1A/NR2A or with an N-terminal fragment of mutant huntingtin.
Conclusions:
- Full-length mutant huntingtin enhances NMDA-induced apoptotic death in cells expressing NR1A/NR2B NMDARs.
- This enhancement, particularly involving NR1A/NR2B, may contribute to the selective neurodegeneration of medium-sized spiny neurons in Huntington's disease.
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