期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：47
页码：E7580-E7589
DOI：10.1073/pnas.1608432113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAnimal models of human diseases provide important tools for mechanistic and preclinical investigations. Mutations in several genes cause ALS. One such gene is ubiquilin 2 (UBQLN2), mutations in which cause dominant inheritance of ALS with frontotemporal dementia (ALS-FTD). Several rodent models carrying UBQLN2 mutations have been described, but none develop motor neuron disease. We describe two transgenic (Tg) mouse models of ALS-FTD carrying different UBQLN2 mutations. Both models develop cognitive deficits, classic TAR-DNA binding protein 43 (TDP-43) pathology seen in ALS, and motor neuron disease. By contrast, Tg mouse lines expressing WT UBQLN2 had normal lifespans, no evidence of TDP-43 pathology, and mild signs of disease. These mouse lines provide valuable investigative tools for ALS-FTD research. 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.
关键词：ALS ; motor neuron disease ; UBQLN2 ; TDP-43 pathology
