Sittler A, Wälter S, Wedemeyer N, Hasenbank R, Scherzinger E, Eickhoff H, Bates G P, Lehrach H, Wanker E E
Max-Planck-Institut für Molekulare Genetik, Berlin, Germany.
Mol Cell. 1998 Oct;2(4):427-36. doi: 10.1016/s1097-2765(00)80142-2.
The mechanism by which aggregated polygins cause the selective neurodegeneration in Huntington's disease (HD) is unknown. Here, we show that the SH3GL3 protein, which is preferentially expressed in brain and testis, selectively interacts with the HD exon 1 protein (HDex1p) containing a glutamine repeat in the pathological range and promotes the formation of insoluble polyglutamine-containing aggregates in vivo. The C-terminal SH3 domain in SH3GL3 and the proline-rich region in HDex1p are essential for the interaction. Coimmunoprecipitations and immunofluorescence studies revealed that SH3GL3 and HDex1p colocalize in transfected COS cells. Additionally, an anti-SH3GL3 antibody was also able to coimmunoprecipitate the full-length huntingtin from an HD human brain extract. The characteristics of the interaction between SH3GL3 and huntingtin and the colocalization of the two proteins suggest that SH3GL3 could be involved in the selective neuronal cell death in HD.
聚集的多聚谷氨酰胺导致亨廷顿舞蹈病（HD）中选择性神经变性的机制尚不清楚。在此，我们表明，在脑和睾丸中优先表达的SH3GL3蛋白，与病理范围内含有谷氨酰胺重复序列的HD外显子1蛋白（HDex1p）选择性相互作用，并在体内促进不溶性含多聚谷氨酰胺聚集体的形成。SH3GL3中的C末端SH3结构域和HDex1p中的富含脯氨酸区域对于这种相互作用至关重要。免疫共沉淀和免疫荧光研究表明，SH3GL3和HDex1p在转染的COS细胞中共定位。此外，抗SH3GL3抗体也能够从HD人脑提取物中免疫共沉淀全长亨廷顿蛋白。SH3GL3与亨廷顿蛋白之间相互作用的特征以及这两种蛋白的共定位表明，SH3GL3可能参与了HD中选择性神经元细胞死亡。
