The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator

Although the linkage of polyglutamine (poly-Q) repeat expansion in the andr ogen receptor (AR) to Kennedy's disease CX-linked spinal and bulbar muscula r atrophy) was a major step forward, the detailed molecular mechanism of ho w the change in poly-Q length contributes to the disease remains unclear. H ere we report the identification of a nuclear G-protein, Ras-related nuclea r protein/ARA24, as the first AR coactivator that can bind differentially w ith different lengths of poly-Q within AR. In the yeast and mammalian recip rocal interacting assays, our data suggested the interaction of AR N-termin al domain with ARA24 diminishes as the poly-Q length increases. The coactiv ation of ARA24 also diminishes with the poly-Q expansion within AR. Deletio n of the acidic hexapeptide (DEDDDL) at the C terminus of ARA24 further enh ances its AR coactivation. Together, our data suggest that poor interaction and weaker coactivation of ARA24 to the longer poly-Q AR in the X-linked s pinal and bulbar muscular atrophied AR could contribute to the weaker trans activation of AR, The con sequence of poor interaction and weak coactivatio n may eventually lead to the partial androgen insensitivity during the deve lopment of Kennedy's disease.