Pathogenic TDP-43 accelerates the generation of toxic exon1 HTT in Huntington's disease knock-in mice

被引：0

作者：

Bai, Dazhang ^{[1
,2
]}

Deng, Fuyu ^{[1
,3
]}

Jia, Qingqing ^{[1
]}

Ou, Kaili ^{[1
]}

Wang, Xiang ^{[1
]}

Hou, Junqi ^{[1
]}

Zhu, Longhong ^{[1
]}

Guo, Mingwei ^{[1
]}

Yang, Su ^{[1
]}

Jiang, Guohui ^{[2
]}

Li, Shihua ^{[1
]}

Li, Xiao-Jiang ^{[1
]}

Yin, Peng ^{[1
]}

机构：

[1] Jinan Univ, Guangdong Hongkong Macau Inst CNS Regenerat, State Key Lab Bioact Mol & Druggabil Assessment, Guangdong Key Lab Nonhuman Primate Res, Guangzhou 510632, Guangdong, Peoples R China

[2] North Sichuan Med Coll, Affiliated Hosp, Inst Neurol Dis, Dept Neurol, Nanchong, Sichuan, Peoples R China

[3] Shenzhen Inst Drug Control, Shenzhen Testing Ctr Med Devices, Vitro Diagnost Reagents Testing Dept, Shenzhen, Guangdong, Peoples R China

来源：

AGING CELL | 2024年 / 23卷 / 12期

基金：

中国国家自然科学基金;

关键词：

aberrant splicing; Huntington's disease; mislocalization; TDP-43; FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS; ENDOPLASMIC-RETICULUM STRESS; NUCLEAR FACTOR TDP-43; BINDING PROTEIN 43; MESSENGER-RNA; MURINE MODEL; MOUSE MODEL; EARLY MOTOR; N-TERMINUS;

D O I：

10.1111/acel.14325

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Huntington's disease (HD) is caused by a CAG repeat expansion in exon1 of the HTT gene that encodes a polyglutamine tract in huntingtin protein. The formation of HTT exon1 fragments with an expanded polyglutamine repeat has been implicated as a key step in the pathogenesis of HD. It was reported that the CAG repeat length-dependent aberrant splicing of exon1 HTT results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP-43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP-43 is mislocalized in the cytoplasm. By investigating HD knock-in mice, we explore whether the pathogenic TDP-43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP-43 without nuclear localization signal. We found that the cytoplasmic TDP-43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP-43, via its binding to the intron1 sequence (GU/UG)n of the mouse Htt pre-mRNA, promotes the transport of exon1-intron1 Htt onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP-43 contributes to HD pathogenesis via its binding to and transport of nuclear un-spliced mRNA to the ribosome for the generation of a toxic protein product.

引用

页数：18