Loss of fused in sarcoma (FUS) promotes pathological Tau splicing

被引：70

作者：

Orozco, Denise ^{[1
,2
]}

Tahirovic, Sabina ^{[1
]}

Rentzsch, Kristin ^{[1
]}

Schwenk, Benjamin M. ^{[1
]}

Haass, Christian ^{[1
,3
]}

Edbauer, Dieter ^{[1
,3
]}

机构：

[1] German Ctr Neurodegenerat Dis DZNE, D-80336 Munich, Germany

[2] Int Max Planck Res Sch Mol & Cellular Life Sci, D-82152 Martinsried, Germany

[3] Univ Munich, Adolf Butenandt Inst, D-80336 Munich, Germany

来源：

EMBO REPORTS | 2012年 / 13卷 / 08期

关键词：

neurodegeneration; FUS; RNA-binding protein; splicing; Tau (MAPT); AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL DEMENTIA; PARKINSONS-DISEASE; MAPT REGION; EXPRESSION; MUTATIONS; PROTEIN; GENE; TDP-43; ACTIVATION;

D O I：

10.1038/embor.2012.90

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A subset of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients present pathological redistribution and aggregation of the nuclear protein fused in sarcoma (FUS) in the cytoplasm. Although FUS associates with the spliceosomal complex, no endogenous neuronal splicing targets have been identified. Here we identify Tau mRNA as a physiological splicing target of FUS. In mouse brain, FUS directly binds to Tau pre-mRNA, and knockdown of FUS in hippocampal neurons leads to preferential inclusion of Tau exons 3 and 10. FUS knockdown causes significant growth cone enlargement and disorganization reminiscent of Tau loss of function. These findings suggest that disturbed cytoskeletal function and enhanced expression of the neurodegeneration-associated Tau exon 10 might contribute to FTLD/ALS with FUS inclusions.

引用

页码：759 / 764

页数：6

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