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

doi:10.1073/pnas.0409402102

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

^*Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390; ^†Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, Children's and Woman's Hospital, University of British Columbia, Vancouver, BC, Canada V6T 1Z4; ^‡Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605; ^§Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016; and ^¶Department of Neuroscience, Weill Medical College of Cornell University, New York, NY 10022

Contributed by Rodolfo Llinás, December 22, 2004

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.

Footnotes

↵ ∥ To whom correspondence should be addressed at: Department of Physiology, K4.112, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040. E-mail: ilya.bezprozvanny{at}utsouthwestern.edu.
Author contributions: R.L., B.S.K., M.R.H., and I.B. designed research; T.-S.T., E.S., V.L., I.G.S., and M.S. performed research; T.-S.T., E.S., V.L., I.G.S., M.S., R.L., M.R.H., and I.B. analyzed data; and B.S.K., M.R.H., and I.B. wrote the paper.
Abbreviations: CPCCOEt, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester; DIV, days in vitro; exp, expansion; HD, Huntington's disease; Htt, huntingtin; InsP₃, inositol 1,4,5-trisphosphate; InsP₃R1, type 1 InsP₃ receptor; MCU, mitochondrial Ca²⁺ uniporter/channel; MPEP, 2-methyl-6-(phenylethynyl)pyridine hydrochloride; MPTP, mitochondrial permeability transition pore; MSN, medium spiny neurons; NMDAR, NMDA receptor; PI, propidium iodide; Ru360, Ruthenium 360.