Diminished hippocalcin expression in Huntington's disease brain does not account for increased striatal neuron vulnerability as assessed in primary neurons.
Hippocalcin is a neuronal calcium sensor protein previously implicated in regulating neuronal viability and plasticity. Hippocalcin is the most highly expressed neuronal calcium sensor in the medium spiny striatal output neurons that degenerate selectively in Huntington's disease (HD). We have previously shown that decreased hippocalcin expression occurs in parallel with the onset of disease phenotype in mouse models of HD. Here we show by in situ hybridization histochemistry that hippocalcin RNA is also diminished by 63% in human HD brain. These findings lead us to hypothesize that diminished hippocalcin expression might contribute to striatal neurodegeneration in HD. We tested this hypothesis by assessing whether restoration of hippocalcin expression would decrease striatal neurodegeneration in cellular models of HD comprising primary striatal neurons exposed to mutant huntingtin, the mitochondrial toxin 3-nitropropionic acid or an excitotoxic concentration of glutamate. Counter to our hypothesis, hippocalcin expression did not improve the survival of striatal neurons under these conditions. Likewise, expression of hippocalcin together with interactor proteins including the neuronal apoptosis inhibitory protein did not increase the survival of striatal cells in cellular models of HD. These results indicate that diminished hippocalcin expression does not contribute to HD-related neurodegeneration.
Rudinskiy
Nikita
N
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Kaneko
Yoshio A
YA
Beesen
Ayshe Ana
AA
Gokce
Ozgun
O
Régulier
Etienne
E
Déglon
Nicole
N
Luthi-Carter
Ruth
R
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics; D000818:Animals; D002421:Caudate Nucleus / Q000473:pathology* / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D018698:Glutamic Acid / Q000633:toxicity; D051597:Hippocalcin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D007668:Kidney / Q000166:cytology; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009498:Neurotoxins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
C496691:HPCA protein, human; C496800:NAIP protein, human; D051616:Neuronal Apoptosis-Inhibitory Protein; D009498:Neurotoxins; D012333:RNA, Messenger; D051597:Hippocalcin; D018698:Glutamic Acid; D015094:3-Hydroxyacyl CoA Dehydrogenases