Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan.
CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan.
Acta Neuropathol Commun. 2015 Apr 25;3:24. doi: 10.1186/s40478-015-0202-6.
FUS/TLS is an RNA-binding protein whose genetic mutations or pathological inclusions are associated with neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor (ET). It is unclear whether their pathogenesis is mediated by gain or loss of function of FUS/TLS.
Here, we established outbred FUS/TLS knockout mice to clarify the effects of FUS/TLS dysfunction in vivo. We obtained homozygous knockout mice that grew into adulthood. Importantly, they did not manifest ALS- or ET-like phenotypes until nearly two years. Instead, they showed distinct histological and behavioral alterations including vacuolation in hippocampus, hyperactivity, and reduction in anxiety-like behavior. Knockout mice showed transcriptome alterations including upregulation of Taf15 and Hnrnpa1, while they have normal morphology of RNA-related granules such as Gems.
Collectively, FUS/TLS depletion causes phenotypes possibly related to neuropsychiatric and neurodegenerative conditions, but distinct from ALS and ET, together with specific alterations in RNA metabolisms.
FUS/TLS 是一种 RNA 结合蛋白，其基因突变或病理性包含物与包括肌萎缩侧索硬化症 (ALS)、额颞叶痴呆和特发性震颤 (ET) 在内的神经退行性疾病有关。其发病机制是通过 FUS/TLS 的功能获得还是丧失来介导的尚不清楚。
在这里，我们建立了远交系 FUS/TLS 敲除小鼠，以阐明 FUS/TLS 功能障碍在体内的作用。我们获得了能够成年的纯合敲除小鼠。重要的是，它们直到近 2 岁才表现出 ALS 或 ET 样表型。相反，它们表现出明显的组织学和行为改变，包括海马空泡化、过度活跃和焦虑样行为减少。敲除小鼠表现出转录组改变，包括 Taf15 和 Hnrnpa1 的上调，而它们的 RNA 相关颗粒（如 Gems）形态正常。
总之，FUS/TLS 缺失导致的表型可能与神经精神和神经退行性疾病有关，但与 ALS 和 ET 不同，同时伴有 RNA 代谢的特定改变。
