Dipartimento di Biologia Animale, Laboratorio di Biologia Cellulare e Neurobiologia, Università di Pavia, via Ferrata 1, 27100 Pavia, Italy.
Exp Neurol. 2011 Dec;232(2):114-8. doi: 10.1016/j.expneurol.2011.08.009. Epub 2011 Aug 16.
In the cerebellum of adult-aging Ts65Dn mice, a murine model of Down syndrome, Purkinje cells undergo degeneration. Searching for the cause of Purkinje cell degeneration, we have studied the ubiquitin-proteasome system (UPS) in the cerebellum of aging Ts65Dn mice. Inhibition of UPS is sufficient to induce neuron degeneration and death. Proteasome chymotrypsin-like proteolytic activity was reduced by 35% in the cerebellum of Ts65Dn mice in comparison with euploid animals. Accordingly, Western blot analysis of ubiquitin showed an increase in ubiquitinated proteins. Immunocytochemistry for ubiquitin revealed strongly positive intranuclear inclusions in Purkinje cells and large neurons of cerebellar nuclei. The Western blot analysis of ubiquitin in nuclear protein extracts confirmed the increase of ubiquitinated proteins in the cell nuclei. After FUS immunocytochemistry, large intranuclear inclusions were visible in Purkinje cells and large neurons of cerebellar nuclei in Ts65Dn mice. Together, data indicate a possible role for proteasome inhibition in the cerebellar neurodegeneration in Ts65Dn mice.
在唐氏综合征的小鼠模型 Ts65Dn 成年期衰老的小脑，浦肯野细胞发生退化。为了寻找浦肯野细胞退化的原因，我们研究了衰老 Ts65Dn 小鼠小脑的泛素-蛋白酶体系统（UPS）。UPS 的抑制足以诱导神经元的退化和死亡。与正常二倍体动物相比，Ts65Dn 小鼠小脑的蛋白酶体糜蛋白酶样蛋白酶活性降低了 35%。相应地，泛素的 Western blot 分析显示泛素化蛋白增加。泛素免疫细胞化学显示浦肯野细胞和小脑核大神经元中的核内强阳性包涵体。核蛋白提取物中泛素的 Western blot 分析证实了核内泛素化蛋白的增加。FUS 免疫细胞化学后，在 Ts65Dn 小鼠的浦肯野细胞和小脑核大神经元中可见大的核内包涵体。这些数据表明，蛋白酶体抑制可能在 Ts65Dn 小鼠的小脑神经退行性变中起作用。
