Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease

TS Tang, E Slow, V Lupu… - Proceedings of the …, 2005 - National Acad Sciences
TS Tang, E Slow, V Lupu, IG Stavrovskaya, M Sugimori, R Llinás, BS Kristal, MR Hayden
Proceedings of the National Academy of Sciences, 2005National Acad Sciences
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 …
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.
National Acad Sciences