Calretinin interacts with huntingtin and reduces mutant huntingtin-caused cytotoxicity.
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.
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.
Gaofeng
G
Dong
Kylie
K
Gross
Fangfang
F
Qiao
Justine
J
Ferguson
Eduardo A
EA
Callegari
Khosrow
K
Rezvani
Dong
D
Zhang
Christian J
CJ
Gloeckner
Marius
M
Ueffing
Hongmin
H
Wang
D000818:Animals; D064032:Calbindin 2; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
C576764:CALB2 protein, human; C576511:Calb2 protein, mouse; D064032:Calbindin 2; D002135:Calcium-Binding Proteins; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D064030:S100 Calcium Binding Protein G