Modelling C9orf72 dipeptide repeat proteins of a physiologically relevant size

被引：28

作者：

Callister, Janis Bennion ^{[1
]}

Ryan, Sarah ^{[1
]}

Sim, Joan ^{[1
]}

Rollinson, Sara ^{[1
]}

Pickering-Brown, Stuart M. ^{[1
]}

机构：

[1] Univ Manchester, Fac Biol Med & Hlth, Div Neurosci & Expt Psychol, AV Hill Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England

来源：

HUMAN MOLECULAR GENETICS | 2016年 / 25卷 / 23期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS; HEXANUCLEOTIDE REPEAT; GGGGCC REPEAT; RNA FOCI; EXPANSION; INCLUSIONS; NEURODEGENERATION; DROSOPHILA; TOXICITY;

D O I：

10.1093/hmg/ddw327

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：

C9orf72 expansions are the most common genetic cause of FTLD and MND identified to date. Although being intronic, the expansion is translated into five different dipeptide repeat proteins (DPRs) that accumulate within patients' neurons. Attempts have been made to model DPRs in cell and animals. However, the majority of these use DPRs repeat numbers much shorter than those observed in patients. To address this we have generated a selection of DPR expression constructs with repeat numbers in excess of 1000 repeats, matching what is seen in patients. Small and larger DPRs produce inclusions with similar morphology but different cellular effects. We demonstrate a length dependent effect using electrophysiology with a phenotype only occurring with the longest DPRs. These data highlight the importance of using physiologically relevant repeat numbers when modelling DPRs.

引用

页码：5069 / 5082

页数：14

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