The C9ORF72 repeat expansion alters neurodevelopment

被引：6

作者：

Hendricks, Eric ^{[1
,2
,3
]}

Quihuis, Alicia M. ^{[3
,4
]}

Hung, Shu-Ting ^{[1
,2
,3
]}

Chang, Jonathan ^{[1
,2
,3
]}

Dorjsuren, Nomongo ^{[1
,2
,3
]}

Der, Balint ^{[1
,2
]}

Staats, Kim A. ^{[1
,2
]}

Shi, Yingxiao ^{[1
,2
,3
]}

Maria, Naomi S. Sta ^{[3
,4
]}

Jacobs, Russell E. ^{[3
,4
]}

Ichida, Justin K. ^{[1
,2
,3
]}

机构：

[1] Univ Southern Calif, Keck Sch Med, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90033 USA

[2] Univ Southern Calif, Eli & Edythe Broad CIRM Ctr Regenerat Med & Stem C, Los Angeles, CA 90033 USA

[3] Univ Southern Calif, Zilkha Neurogenet Inst, Keck Sch Med, Los Angeles, CA 90033 USA

[4] Univ Southern Calif, Keck Sch Med, Dept Physiol & Neurosci, Los Angeles, CA 90033 USA

来源：

CELL REPORTS | 2023年 / 42卷 / 08期

关键词：

C9ORF72; EXPANSION; RNA FOCI; HEXANUCLEOTIDE REPEAT; MOTOR DEFICITS; MOUSE; CELLS; ALS; NEURODEGENERATION; DEGENERATION; PROTEINS;

D O I：

10.1016/j.celrep.2023.112983

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Genetic mutations that cause adult-onset neurodegenerative diseases are often expressed during embryonic stages, but it is unclear whether they alter neurodevelopment and how this might influence disease onset. Here, we show that the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), a repeat expansion in C9ORF72 , restricts neural stem cell proliferation and reduces cortical and thalamic size in utero. Surprisingly, a repeat expansion-derived dipeptide repeat protein (DPR) not known to reduce neuronal viability plays a key role in impairing neurodevelopment. Pharmacologically mimicking the effects of the repeat expansion on neurodevelopment increases susceptibility of C9ORF72 mice to motor defects. Thus, the C9ORF72 repeat expansion stunts development of the brain regions prominently affected in C9ORF72 FTD/ALS patients.

引用

页数：24

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