Qin Zheng-Hong, Wang Yumei, Sapp Ellen, Cuiffo Benjamin, Wanker Erich, Hayden Michael R, Kegel Kimberly B, Aronin Neil, DiFiglia Marian
Laboratory of Cellular Neurobiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
J Neurosci. 2004 Jan 7;24(1):269-81. doi: 10.1523/JNEUROSCI.1409-03.2004.
Polyglutamine expansion in the N terminus of huntingtin (htt) causes selective neuronal dysfunction and cell death by unknown mechanisms. Truncated htt expressed in vitro produced htt immunoreactive cytoplasmic bodies (htt bodies). The fibrillar core of the mutant htt body resisted protease treatment and contained cathepsin D, ubiquitin, and heat shock protein (HSP) 40. The shell of the htt body was composed of globules 14-34 nm in diameter and was protease sensitive. HSP70, proteasome, dynamin, and the htt binding partners htt interacting protein 1 (HIP1), SH3-containing Grb2-like protein (SH3GL3), and 14.7K-interacting protein were reduced in their normal location and redistributed to the shell. Removal of a series of prolines adjacent to the polyglutamine region in htt blocked formation of the shell of the htt body and redistribution of dynamin, HIP1, SH3GL3, and proteasome to it. Internalization of transferrin was impaired in cells that formed htt bodies. In cortical neurons of Huntington's disease patients with early stage pathology, dynamin immunoreactivity accumulated in cytoplasmic bodies. Results suggest that accumulation of a nonfibrillar form of mutant htt in the cytoplasm contributes to neuronal dysfunction by sequestering proteins involved in vesicle trafficking.
亨廷顿蛋白（htt）N端的聚谷氨酰胺扩增通过未知机制导致选择性神经元功能障碍和细胞死亡。体外表达的截短型htt产生了htt免疫反应性胞质体（htt体）。突变型htt体的纤维状核心对蛋白酶处理具有抗性，并且含有组织蛋白酶D、泛素和热休克蛋白（HSP）40。htt体的外壳由直径为14 - 34 nm的小球组成，对蛋白酶敏感。HSP70、蛋白酶体、发动蛋白以及htt结合伴侣htt相互作用蛋白1（HIP1）、含SH3结构域的类Grb2蛋白（SH3GL3）和14.7K相互作用蛋白在其正常位置减少，并重新分布到外壳。去除htt中聚谷氨酰胺区域附近的一系列脯氨酸可阻止htt体外壳的形成以及发动蛋白、HIP1、SH3GL3和蛋白酶体向其重新分布。在形成htt体的细胞中，转铁蛋白的内化受损。在早期病理阶段的亨廷顿病患者的皮质神经元中，发动蛋白免疫反应性积聚在胞质体中。结果表明，细胞质中突变型htt的非纤维状形式的积累通过隔离参与囊泡运输的蛋白质而导致神经元功能障碍。
