SH3GL3 ASSOCIATES WITH THE HUNTINGTIN EXON-1 PROTEIN AND PROMOTES THEFORMATION OF POLYGLN-CONTAINING PROTEIN AGGREGATES

The mechanism by which aggregated polyglns cause the selective neurode generation in Huntington's disease (HD) is unknown. Here, we show that the SH3GL3 protein, which is preferentially expressed in brain and te stis, selectively interacts with the HD exon 1 protein (HDex1p) contai ning a glutamine repeat in the pathological range and promotes the for mation of insoluble polyglutamine-containing aggregates in vivo. The C -terminal SH3 domain in SH3GL3 and the proline-rich region in HDex1p a re essential for the interaction. Coimmunoprecipitations and immunoflu orescence studies revealed that SH3GL3 and HDex1p colocalize in transf ected COS cells. Additionally, an anti-SH3GL3 antibody was also able t o coimmunoprecipitate the full-length huntingtin from an HD human brai n extract. The characteristics of the interaction between SH3GL3 and h untingtin and the colocalization of the two proteins suggest that SH3G L3 could be involved in the selective neuronal cell death in HD.