Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease.
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.
Tang
Tie-Shan
TS
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Slow
Elizabeth
E
Lupu
Vitalie
V
Stavrovskaya
Irina G
IG
Sugimori
Mutsuyuki
M
Llinás
Rodolfo
R
Kristal
Bruce S
BS
Hayden
Michael R
MR
Bezprozvanny
Ilya
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000008:administration & dosage; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D018698:Glutamic Acid