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Calcineurin is involved in the early activation of NMDA‐mediated cell death in mutant huntingtin knock‐in striatal cells
Author(s) -
Xifró Xavier,
GarcíaMartínez Juan Manuel,
Del Toro Daniel,
Alberch Jordi,
PérezNavarro Esther
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05252.x
Subject(s) - huntingtin , excitotoxicity , calcineurin , transfection , huntingtin protein , microbiology and biotechnology , mutant , biology , programmed cell death , cell culture , apoptosis , biochemistry , transplantation , genetics , medicine , gene
Excitotoxicity has been proposed as one of the mechanisms involved in the specific loss of striatal neurons that occurs in Huntington’s disease. Here, we studied the role of calcineurin in the vulnerability of striatal neurons expressing mutant huntingtin to excitotoxicity. To this end, we induced excitotoxicity by adding NMDA to a striatal precursor cell line expressing full‐length wild‐type (STHdh Q7/Q7 ) or mutant (STHdh Q111/Q111 ) huntingtin. We observed that cell death appeared earlier in STHdh Q111/Q111 cells than in STHdh Q7/Q7 cells. Interestingly, these former cells expressed higher levels of calcineurin A that resulted in a greater increase of its activity after NMDA receptor stimulation. Moreover, transfection of full‐length mutant huntingtin in different striatal‐derived cells (STHdh Q7/Q7 , M213 and primary cultures) increased calcineurin A protein levels. To determine whether high levels of calcineurin A might account for the earlier activation of cell death in mutant huntingtin knock‐in cells, wild‐type cells were transfected with calcineurin A. Calcineurin A‐transfected STHdh Q7/Q7 cells displayed a significant increase in cell death compared with that recorded in green fluorescent protein‐transfected cells after NMDA treatment. Notably, addition of the calcineurin inhibitor FK‐506 produced a more robust reduction in cell death in mutant huntingtin knock‐in cells than it did in wild‐type cells. These results suggest that high levels of calcineurin A could account for the increased vulnerability of striatal cells expressing mutant huntingtin to excitotoxicity.