Saudou F, Finkbeiner S, Devys D, Greenberg M E
Department of Neurology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cell. 1998 Oct 2;95(1):55-66. doi: 10.1016/s0092-8674(00)81782-1.
The mechanisms by which mutant huntingtin induces neurodegeneration were investigated using a cellular model that recapitulates features of neurodegeneration seen in Huntington's disease. When transfected into cultured striatal neurons, mutant huntingtin induces neurodegeneration by an apoptotic mechanism. Antiapoptotic compounds or neurotrophic factors protected neurons against mutant huntingtin. Blocking nuclear localization of mutant huntingtin suppressed its ability to form intranuclear inclusions and to induce neurodegeneration. However, the presence of inclusions did not correlate with huntingtin-induced death. The exposure of mutant huntingtin-transfected striatal neurons to conditions that suppress the formation of inclusions resulted in an increase in mutant huntingtin-induced death. These findings suggest that mutant huntingtin acts within the nucleus to induce neurodegeneration. However, intranuclear inclusions may reflect a cellular mechanism to protect against huntingtin-induced cell death.
利用一种重现亨廷顿舞蹈症中所见神经退行性变特征的细胞模型，研究了突变型亨廷顿蛋白诱导神经退行性变的机制。当转染到培养的纹状体神经元中时，突变型亨廷顿蛋白通过凋亡机制诱导神经退行性变。抗凋亡化合物或神经营养因子可保护神经元免受突变型亨廷顿蛋白的影响。阻断突变型亨廷顿蛋白的核定位可抑制其形成核内包涵体和诱导神经退行性变的能力。然而，包涵体的存在与亨廷顿蛋白诱导的死亡并无关联。将转染了突变型亨廷顿蛋白的纹状体神经元暴露于抑制包涵体形成的条件下，会导致突变型亨廷顿蛋白诱导的死亡增加。这些发现表明，突变型亨廷顿蛋白在细胞核内起作用以诱导神经退行性变。然而，核内包涵体可能反映了一种防止亨廷顿蛋白诱导细胞死亡的细胞机制。
