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DOI | 10.1126/science.aav2606 |
Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity | |
Zhang, Yong-Jie1; 39;Raw, Aliesha D.2 | |
2019-02-15 | |
发表期刊 | SCIENCE
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ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2019 |
卷号 | 363期号:6428页码:707-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | How hexanucleotide GGGGCC (G(4)C(2)) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G(4)C(2) repeats. The expression of green fluorescent protein-conjugated (PR)(50) (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1 alpha (HP1 alpha) liquid-phase disruptions, decreases in HP1 alpha expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1 alpha, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000458874100023 |
WOS关键词 | HEXANUCLEOTIDE REPEAT ; PHASE-SEPARATION ; ANTISENSE TRANSCRIPTS ; GGGGCC REPEAT ; EXPANSION ; PROTEINS ; NEURODEGENERATION ; TRANSLATION ; FOCI ; DYSFUNCTION |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/200768 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA; 2.Mayo Clin, Grad Sch Biomed Sci, Grad Program Neurosci, Jacksonville, FL 32224 USA; 3.Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Philadelphia, PA 19104 USA; 4.Univ Colorado, Inst Behav Genet, Dept Integrat Physiol, Boulder, CO 80309 USA; 5.NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA; 6.Univ Calif San Francisco, Dept Biochem & Biophys, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA; 7.Chan Zuckerberg Biohub, San Francisco, CA USA; 8.Biogen Idec Inc, Prot Chem, Cambridge, MA USA; 9.Biogen Idec Inc, Neurol Res, Cambridge, MA USA; 10.Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA; 11.Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA; 12.Scholar Rock, Antibody Discovery, Cambridge, MA USA |
推荐引用方式 GB/T 7714 | Zhang, Yong-Jie,39;Raw, Aliesha D.. Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity[J]. SCIENCE,2019,363(6428):707-+. |
APA | Zhang, Yong-Jie,&39;Raw, Aliesha D..(2019).Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity.SCIENCE,363(6428),707-+. |
MLA | Zhang, Yong-Jie,et al."Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity".SCIENCE 363.6428(2019):707-+. |
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