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 b y the expansion of the polyglutamine (polyGln) tract in the human androgen receptor (hAR). One mechanism by which polyGin-expanded proteins are believ ed to cause neuronotoxicity is through aberrant interaction(s) with, and po ssible sequestration of, critical cellular protein(s). Our goal was to conf irm and further characterize the interaction between hAR and cytochrome c o xidase subunit Vb (COXVb), a nuclear-encoded mitochondrial protein. We init ially isolated COXVb as an AR-interacting protein in a yeast two-hybrid scr een to identify candidate proteins that interacted with normal and polyGin- expanded AR. Using the mammalian two-hybrid system, we confirm that COXVb i nteracts with normal and mutant AR and demonstrated that the COXVb-normal A R interaction is stimulated by heat shock protein 70. In addition, blue flu orescent protein-tagged AR specifically co-localized with cytoplasmic aggre gates formed by green fluorescent protein-labeled polyGin-expanded AR in an drogen-treated cells. Mitochondrial dysfunction may precede neuropathologic al findings in polyGin-expanded disorders and may thus represent an early e vent in neuronotoxicity. Interaction of COXVb and hAR, with subsequent sequ estration of COXVb, may provide a mechanism for putative mitochondrial dysf unction in SBMA. (C) 2001 Elsevier Science Inc.