Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations
Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations
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DOI：
10.1073/pnas.1608432113
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发表时间：
2016-11-22
影响因子：
11.1
通讯作者：
Monteiro, Mervyn J.
中科院分区：
文献类型：
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作者：
Le, Nhat T. T.;Chang, Lydia;Monteiro, Mervyn J.
泛素2（UBQLN 2）的错义突变导致ALS伴额颞叶痴呆（ALS-FTD）。ALS的动物模型对于理解发病机制和临床前研究是有用的。然而，先前携带UBQLN 2突变的啮齿动物模型未能表现出任何运动神经元疾病的迹象。在这里，我们发现表达ALS-FTD连接的P497 S或P506 T UBQLN 2突变的小鼠品系具有认知缺陷、寿命缩短并发生运动神经元疾病，与人类疾病相似。对患有终末期疾病的小鼠的神经病理学分析揭示了泛素化包涵体在脑和脊髓中的积累、星形细胞增多、海马神经元数量的减少以及细胞核中TAR-DNA结合蛋白43的染色减少，伴随着脊髓运动神经元的细胞质中泛素（+）包涵体的形成。此外，两条线显示去神经肌肉萎缩和年龄依赖性的运动神经元的损失，与大口径轴突的数量减少。相比之下，表达WT UBQLN 2的两个小鼠系大多没有疾病的临床和病理学体征。这些UBQLN 2小鼠模型为鉴定ALS-FTD发病机制和研究阻止疾病的治疗策略提供了有价值的工具。
Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin(+) inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.