Disturbed Ca <sup>2+</sup> signaling and apoptosis of medium spiny neurons in Huntington's disease
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Abstract
Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin. Here, we used a yeast artificial chromosome (YAC) transgenic mouse model of HD to investigate the connection between disturbed calcium (Ca2+) signaling and apoptosis of HD medium spiny neurons (MSN). Repetitive application of glutamate elevates cytosolic Ca2+ levels in MSN from the YAC128 mouse but not in MSN from the wild-type or control YAC18 mouse. Application of glutamate results in apoptosis of YAC128 MSN but not wild-type or YAC18 MSN. Analysis of glutamate-induced apoptosis of the YAC128 MSN revealed that (i) actions of glutamate are mediated by mGluR1/5 and NR2B glutamate receptors; (ii) membrane-permeable inositol 1,4,5-trisphosphate receptor blockers 2-APB and Enoxaparin (Lovenox) are neuroprotective; (iii) apoptosis involves the intrinsic pathway mediated by release of mitochondrial cytochrome c and activation of caspases 9 and 3; (iv) apoptosis requires mitochondrial Ca2+ overload and can be prevented by the mitochondrial Ca2+ uniporter blocker Ruthenium 360; and (v) apoptosis involves opening of mitochondrial permeability transition pore (MPTP) and can be prevented by MPTP blockers such as bongkrekic acid, Nortriptyline, Desipramine, Trifluoperazine, and Maprotiline. These findings describe a pathway directly linking disturbed Ca2+ signaling and degeneration of MSN in the caudate nucleus in HD. These findings also suggest that Ca2+ and MPTP blockers may have a therapeutic potential for treatment of HD.
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The record
- Venue
- Proceedings of the National Academy of Sciences
- Topic
- Genetic Neurodegenerative Diseases
- Field
- Neuroscience
- Canadian institutions
- —
- Funders
- National Institute of Neurological Disorders and StrokeCure Huntington's Disease InitiativeHereditary Disease FoundationCanadian Institutes of Health ResearchWelch Foundation
- Keywords
- Mitochondrial permeability transition poreMPTPMedium spiny neuronCell biologyGlutamate receptorBiologyApoptosisHuntington's diseaseCytochrome cChemistryMitochondrionBiochemistryProgrammed cell deathReceptorNeuroscienceInternal medicine
- Has abstract in OpenAlex
- yes