Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
J Neurosci. 2010 Aug 4;30(31):10541-50. doi: 10.1523/JNEUROSCI.0146-10.2010.
An expanded polyglutamine (polyQ) stretch in the protein huntingtin (htt) induces self-aggregation into inclusion bodies (IBs) and causes Huntington's disease (HD). Defining precise relationships between early observable variables and neuronal death at the molecular and cellular levels should improve our understanding of HD pathogenesis. Here, we used an automated microscope that tracks thousands of neurons individually over their entire lifetime to quantify interconnected relationships between early variables, such as htt levels, polyQ length, and IB formation, and neuronal death in a primary striatal model of HD. The resulting model revealed that mutant htt increases the risk of death by tonically interfering with homeostatic coping mechanisms rather than producing accumulated damage to the neuron, htt toxicity is saturable, the rate-limiting steps for inclusion body formation and death can be traced to different conformational changes in monomeric htt, and IB formation reduces the impact of the starting levels of htt of a neuron on its risk of death. Finally, the model that emerges from our quantitative measurements places critical limits on the potential mechanisms by which mutant htt might induce neurodegeneration, which should help direct future research.
在蛋白质亨廷顿（htt）中扩展的多聚谷氨酰胺（polyQ）延伸诱导自身聚合形成包含体（IBs），并导致亨廷顿病（HD）。定义早期可观察变量与分子和细胞水平上神经元死亡之间的精确关系，应能提高我们对 HD 发病机制的理解。在这里，我们使用了一种自动显微镜，该显微镜可以在整个生命周期中跟踪数千个神经元，以量化原发性纹状体 HD 模型中早期变量（如 htt 水平、polyQ 长度和 IB 形成）与神经元死亡之间的相互关系。该模型揭示了突变 htt 通过持续干扰体内平衡应对机制而增加死亡风险，而不是对神经元产生累积性损伤，htt 毒性是可饱和的，包含体形成和死亡的限速步骤可追溯到单体 htt 的不同构象变化，并且 IB 形成降低了神经元起始 htt 水平对其死亡风险的影响。最后，我们的定量测量得出的模型对突变 htt 诱导神经退行性变的潜在机制施加了关键限制，这应该有助于指导未来的研究。
