Gusella James F, MacDonald Marcy E
Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, 185 Cambridge Street, Boston, MA 02114, USA.
Trends Biochem Sci. 2006 Sep;31(9):533-40. doi: 10.1016/j.tibs.2006.06.009. Epub 2006 Jul 10.
Thirteen years ago, the culmination of genetic rather than biochemical strategies resulted in the identification of the root cause of Huntington's disease: an expanded CAG trinucleotide repeat that leads to an elongated polyglutamine tract in the huntingtin protein. Since then, biochemical and cell biological attempts to elucidate pathogenesis have largely focused on N-terminal polyglutamine-containing huntingtin fragments. However, continued application of genetic strategies has suggested that the disease process is, in fact, triggered by the presence of expanded polyglutamine in intact huntingtin. An increased emphasis on the earliest presymptomatic stages of the disease, facilitated by incorporating genetic lessons from human patients into the search for biochemical targets, could provide a route to a rational treatment to prevent or slow the onset of this devastating neurodegenerative disorder.
13年前，遗传学而非生物化学策略的成果是确定了亨廷顿舞蹈症的根本病因：一个CAG三核苷酸重复序列的扩增，导致亨廷顿蛋白中多聚谷氨酰胺链延长。从那时起，为阐明发病机制而进行的生物化学和细胞生物学研究主要集中在含多聚谷氨酰胺的亨廷顿蛋白N端片段上。然而，遗传学策略的持续应用表明，事实上，疾病进程是由完整的亨廷顿蛋白中扩增的多聚谷氨酰胺引发的。通过将人类患者的遗传学经验纳入寻找生物化学靶点的研究中，对疾病最早的症状前阶段给予更多关注，可能会为预防或延缓这种毁灭性神经退行性疾病的发病提供一种合理的治疗途径。
