Wetzel Monica K, Naska Sibel, Laliberté Christine L, Rymar Vladimir V, Fujitani Masashi, Biernaskie Jeffrey A, Cole Christy J, Lerch Jason P, Spring Shoshana, Wang S-H, Frankland Paul W, Henkelman R Mark, Josselyn Sheena A, Sadikot Abbas F, Miller Freda D, Kaplan David R
Cell Biology, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A2B4, Canada.
Neuron. 2008 Sep 11;59(5):708-21. doi: 10.1016/j.neuron.2008.07.021.
The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/- mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/- mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/- neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders.
调节神经退行性变的遗传机制目前仍知之甚少。我们发现，p53家族成员p73的一个等位基因缺失会使小鼠因衰老或阿尔茨海默病（AD）而易于发生神经退行性变。行为分析表明，年老而非年轻的p73+/-小鼠表现出运动和认知功能减退、中枢神经系统萎缩以及神经元变性。出乎意料的是，老年p73+/-小鼠的大脑显示出磷酸化tau蛋白（P-tau）阳性细丝的大量积累。此外，当与表达突变淀粉样前体蛋白的AD小鼠模型杂交时，这些小鼠的大脑显示出神经元变性以及含有P-tau的缠结样结构的早期且大量形成。P-tau的增加可能由JNK介导；在p73+/-神经元中，p73靶标JNK的活性增强，且JNK调节P-tau水平。因此，p73对于预防神经退行性变至关重要，p73单倍剂量不足可能是AD和其他神经退行性疾病的一个易感因素。
