Cytochrome c oxidase subunit Vb interacts with human androgen receptor: a potential mechanism for neurotoxicity in spinobulbar muscular atrophy.
Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of the polyglutamine (polyGln) tract in the human androgen receptor (hAR). One mechanism by which polyGln-expanded proteins are believed to cause neuronotoxicity is through aberrant interaction(s) with, and possible sequestration of, critical cellular protein(s). Our goal was to confirm and further characterize the interaction between hAR and cytochrome c oxidase subunit Vb (COXVb), a nuclear-encoded mitochondrial protein. We initially isolated COXVb as an AR-interacting protein in a yeast two-hybrid screen to identify candidate proteins that interacted with normal and polyGln-expanded AR. Using the mammalian two-hybrid system, we confirm that COXVb interacts with normal and mutant AR and demonstrated that the COXVb-normal AR interaction is stimulated by heat shock protein 70. In addition, blue fluorescent protein-tagged AR specifically co-localized with cytoplasmic aggregates formed by green fluorescent protein-labeled polyGln-expanded AR in androgen-treated cells. Mitochondrial dysfunction may precede neuropathological findings in polyGln-expanded disorders and may thus represent an early event in neuronotoxicity. Interaction of COXVb and hAR, with subsequent sequestration of COXVb, may provide a mechanism for putative mitochondrial dysfunction in SBMA.
Beauchemin
A M
AM
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada.
Gottlieb
B
B
Beitel
L K
LK
Elhaji
Y A
YA
Pinsky
L
L
Trifiro
M A
MA
D000818:Animals; D019556:COS Cells; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D008322:Mammals; D008928:Mitochondria / Q000378:metabolism; D020966:Muscular Disorders, Atrophic / Q000235:genetics* / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D019680:Trinucleotide Repeat Expansion; D020798:Two-Hybrid System Techniques
D018840:HSP70 Heat-Shock Proteins; D006728:Hormones; D007202:Indicators and Reagents; D008164:Luminescent Proteins; D010455:Peptides; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; C409504:blue fluorescent protein, Aequorea victoria; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D003576:Electron Transport Complex IV