Overexpression of UBQLN1 reduces neuropathology in the P497S UBQLN2 mouse model of ALS/FTD.
Overexpression of UBQLN1 reduces neuropathology in the P497S UBQLN2 mouse model of ALS/FTD.
复制标题
DOI：
10.1186/s40478-020-01039-9
复制
发表时间：
2020-10-07
影响因子：
7.1
通讯作者：
Monteiro MJ
中科院分区：
文献类型：
--
作者：
Wang S;Tatman M;Monteiro MJ
UBQLN 2错义突变导致肌萎缩侧索硬化伴额颞叶痴呆（ALS/FTD）的X连锁显性遗传UBQLN 2属于人类表达的四种高度同源的蛋白质家族，在维持蛋白质稳态中发挥不同的作用，但一种亚型是否可以取代另一种亚型尚不清楚。在此，我们通过将表达两种蛋白质的转基因（Tg）小鼠品系杂交，并使用一系列病理和行为测试表征所得基因型，检测UBQLN 1过表达是否可以减轻ALS/FTD的P497 S UBQLN 2小鼠模型中的疾病。病理结果显示，与单P497 S Tg小鼠相比，UBQLN 1过表达显著降低了双Tg小鼠中UBQLN 2包涵体的负担、神经元损失和蛋白质稳态紊乱。UBQLN 1过表达的有益作用主要通过在雄性而不是雌性小鼠中的转棒性能和握力中观察到的行为改善来证实。奇怪的是，尽管UBQLN 1过表达减少了P497 S Tg小鼠的疾病病理特征，但雌性小鼠的体重减轻百分比大于雄性小鼠，这与雌性小鼠相应缺乏行为改善相关。这些发现使我们推测，上调UBQLN 1表达的方法可能会降低UBQLN 2突变引起的致病性，但也可能导致性别特异性结果，必须仔细权衡UBQLN 1上调的治疗益处。本文的在线版本（10.1186/s40478-020-01039-9）包含补充材料，可供授权用户使用。
Missense mutations in UBQLN2 cause X-linked dominant inheritance of amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). UBQLN2 belongs to a family of four highly homologous proteins expressed in humans that play diverse roles in maintaining proteostasis, but whether one isoform can substitute for another is not known. Here, we tested whether overexpression of UBQLN1 can alleviate disease in the P497S UBQLN2 mouse model of ALS/FTD by crossing transgenic (Tg) mouse lines expressing the two proteins and characterizing the resulting genotypes using a battery of pathologic and behavioral tests. The pathologic findings revealed UBQLN1 overexpression dramatically reduced the burden of UBQLN2 inclusions, neuronal loss and disturbances in proteostasis in double Tg mice compared to single P497S Tg mice. The beneficial effects of UBQLN1 overexpression were primarily confirmed by behavioral improvements seen in rotarod performance and grip strength in male, but not female mice. Paradoxically, although UBQLN1 overexpression reduced pathologic signatures of disease in P497S Tg mice, female mice had larger percentage of body weight loss than males, and this correlated with a corresponding lack of behavioral improvements in the females. These findings lead us to speculate that methods to upregulate UBQLN1 expression may reduce pathogenicity caused by UBQLN2 mutations, but may also lead to gender-specific outcomes that will have to be carefully weighed with the therapeutic benefits of UBQLN1 upregulation. The online version of this article (10.1186/s40478-020-01039-9) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
泛素蛋白的鉴定，这是一种新型的presenilin相互作用者，可增加Presenilin蛋白的积累。
影响因子：
7.8
作者：
Mah, A L;Perry, G;Smith, M A;Monteiro, M J
通讯作者：
Monteiro, M J
影响因子：
15.1
作者：
Ceballos-Diaz C;Rosario AM;Park HJ;Chakrabarty P;Sacino A;Cruz PE;Siemienski Z;Lara N;Moran C;Ravelo N;Golde TE;McFarland NR
通讯作者：
McFarland NR
影响因子：
16
作者：
Kleijnen, MF;Shih, AH;Howley, PM
通讯作者：
Howley, PM
DOI：
10.1073/pnas.1608432113
发表时间：
2016-11-22
影响因子：
11.1
作者：
Le, Nhat T. T.;Chang, Lydia;Monteiro, Mervyn J.
通讯作者：
Monteiro, Mervyn J.