Reduced calcineurin protein levels and activity in exon-1 mouse models of Huntington's disease: role in excitotoxicity.
Calcineurin is a serine/threonine phosphatase involved in the regulation of glutamate receptors signaling. Here, we analyzed whether the regulation of calcineurin protein levels and activity modulates the susceptibility of striatal neurons to excitotoxicity in R6/1 and R6/1:BDNF+/- mouse models of Huntington's disease. We show that calcineurin inhibition in wild-type mice drastically reduced quinolinic acid-induced striatal cell death. Moreover, calcineurin A and B were differentially regulated during disease progression with a specific reduction of calcineurin A protein levels and calcineurin activity at the onset of the disease in R6/1:BDNF+/- mice. Analysis of the conditional mouse model Tet/HD94 showed that mutant huntingtin specifically controls calcineurin A protein levels. Finally, calcineurin activation induced by intrastriatal quinolinic acid injection in R6/1 mouse was lower than in wild-type mice. Therefore, reduction of calcineurin activity by alteration of calcineurin A expression participates in the pathophysiology of Huntington's disease and contributes to the excitotoxic resistance observed in exon-1 mouse models.
Xifró
Xavier
X
Departament de Biologia Cel.lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, IDIBAPS, Casanova 143, E-08036 Barcelona, Spain.
Giralt
Albert
A
Saavedra
Ana
A
García-Martínez
Juan M
JM
Díaz-Hernández
Miguel
M
Lucas
José J
JJ
Alberch
Jordi
J
Pérez-Navarro
Esther
E
D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017378:Quinolinic Acid / Q000633:toxicity; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D065095:Calcineurin Inhibitors; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009687:Nuclear Proteins; D019703:Calcineurin; D017378:Quinolinic Acid