FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis.
FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis.
复制标题
DOI：
10.1186/s40478-015-0202-6
复制
发表时间：
2015-04-25
影响因子：
7.1
通讯作者：
Nukina N
中科院分区：
文献类型：
--
作者：
Kino Y;Washizu C;Kurosawa M;Yamada M;Miyazaki H;Akagi T;Hashikawa T;Doi H;Takumi T;Hicks GG;Hattori N;Shimogori T;Nukina N
FUS/TLS是一种RNA结合蛋白，其基因突变或病理性包涵体与神经系统疾病相关，包括肌萎缩侧索硬化症（ALS）、额颞叶变性和原发性震颤（ET）。目前尚不清楚其发病机制是否由FUS/TLS功能的获得或丧失介导。在这里，我们建立了远交FUS/TLS基因敲除小鼠，以阐明体内FUS/TLS功能障碍的影响。我们获得了纯合子基因敲除小鼠，这些小鼠长大成人。重要的是，他们直到近两年才表现出ALS或ET样表型。相反，他们表现出明显的组织学和行为学改变，包括海马空泡化、多动和焦虑样行为减少。敲除小鼠表现出转录组改变，包括Taf 15和Hnrnpa 1的上调，而它们具有RNA相关颗粒的正常形态，如Gems。总的来说，FUS/TLS耗竭导致可能与神经精神和神经退行性疾病相关的表型，但与ALS和ET不同，以及RNA代谢的特定改变。本文的在线版本（doi：10.1186/s40478-015-0202-6）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s40478-015-0202-6) contains supplementary material, which is available to authorized users.
登录
查看更多内容
DOI：
10.1074/jbc.m113.492017
发表时间：
2013-08-30
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Shelkovnikova TA;Peters OM;Deykin AV;Connor-Robson N;Robinson H;Ustyugov AA;Bachurin SO;Ermolkevich TG;Goldman IL;Sadchikova ER;Kovrazhkina EA;Skvortsova VI;Ling SC;Da Cruz S;Parone PA;Buchman VL;Ninkina NN
通讯作者：
Ninkina NN
影响因子：
168.9
作者：
Williams, Nigel M.;Zaharieva, Irina;Martin, Andrew;Langley, Kate;Mantripragada, Kiran;Fossdal, Ragnheidur;Stefansson, Hreinn;Stefansson, Karl;Magnusson, Pall;Gudmundsson, Olafur O.;Gustafsson, Omar;Holmans, Peter;Owen, Michael J.;O'Donovan, Michael;Thapar, Anita
通讯作者：
Thapar, Anita
影响因子：
14.5
作者：
Neumann, Manuela;Bentmann, Eva;Mackenzie, Ian R. A.
通讯作者：
Mackenzie, Ian R. A.
影响因子：
12.7
作者：
Mitchell JC;McGoldrick P;Vance C;Hortobagyi T;Sreedharan J;Rogelj B;Tudor EL;Smith BN;Klasen C;Miller CC;Cooper JD;Greensmith L;Shaw CE
通讯作者：
Shaw CE
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.