TY - JOUR
T1 - Calretinin interacts with huntingtin and reduces mutant huntingtin-caused cytotoxicity
AU - Dong, Gaofeng
AU - Gross, Kylie
AU - Qiao, Fangfang
AU - Ferguson, Justine
AU - Callegari, Eduardo A.
AU - Rezvani, Khosrow
AU - Zhang, Dong
AU - Gloeckner, Christian J.
AU - Ueffing, Marius
AU - Wang, Hongmin
PY - 2012/11
Y1 - 2012/11
N2 - Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expansion of CAG trinucleotide repeats encoding for polyglutamine (polyQ) in the huntingtin (Htt) gene. Despite considerable effort, the mechanisms underlying the toxicity of the mutated Htt protein remains largely uncertain. To identify novel therapeutic targets, we recently employed the approach of tandem affinity purification and discovered that calretinin (Cr), a member of the EF-hand family of calcium-binding proteins, is preferentially associated with mHtt, although it also interacts with wild-type Htt. These observations were supported by coimmunoprecipitation and by colocalization of Cr with mHtt in neuronal cultures. Over- expression of Cr reduced mHtt-caused cytotoxicity in both non-neuronal and neuronal cell models of HD, whereas knockdown of Cr expression in the cells enhanced mHtt-caused neuronal cell death. In addition, over-expression of Cr was also associated with reduction of intracellular free calcium and activation of Akt. These results suggest that Cr may be a potential therapeutic target for treatment of HD. Although previous studies have shown that calretinin (Cr), a calcium-binding protein, is associated with neuronal survival in Huntington's disease patients and in different models of the disease, direct physical and functional connections between Cr and mutant huntingtin (mHtt) are lacking. Here, we show that Cr interacts with mHtt and reduces mHtt-caused cytotoxicity in both non-neuronal and neuronal cell models of HD. These results suggest that Cr may be a potential therapeutic target for treatment of HD.
AB - Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expansion of CAG trinucleotide repeats encoding for polyglutamine (polyQ) in the huntingtin (Htt) gene. Despite considerable effort, the mechanisms underlying the toxicity of the mutated Htt protein remains largely uncertain. To identify novel therapeutic targets, we recently employed the approach of tandem affinity purification and discovered that calretinin (Cr), a member of the EF-hand family of calcium-binding proteins, is preferentially associated with mHtt, although it also interacts with wild-type Htt. These observations were supported by coimmunoprecipitation and by colocalization of Cr with mHtt in neuronal cultures. Over- expression of Cr reduced mHtt-caused cytotoxicity in both non-neuronal and neuronal cell models of HD, whereas knockdown of Cr expression in the cells enhanced mHtt-caused neuronal cell death. In addition, over-expression of Cr was also associated with reduction of intracellular free calcium and activation of Akt. These results suggest that Cr may be a potential therapeutic target for treatment of HD. Although previous studies have shown that calretinin (Cr), a calcium-binding protein, is associated with neuronal survival in Huntington's disease patients and in different models of the disease, direct physical and functional connections between Cr and mutant huntingtin (mHtt) are lacking. Here, we show that Cr interacts with mHtt and reduces mHtt-caused cytotoxicity in both non-neuronal and neuronal cell models of HD. These results suggest that Cr may be a potential therapeutic target for treatment of HD.
KW - Huntington's disease
KW - calcium-binding protein
KW - calretinin
KW - huntingtin
KW - neuroprotection
KW - polyglutamine
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U2 - 10.1111/j.1471-4159.2012.07919.x
DO - 10.1111/j.1471-4159.2012.07919.x
M3 - Article
C2 - 22891683
AN - SCOPUS:84867337665
SN - 0022-3042
VL - 123
SP - 437
EP - 446
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 3
ER -