The C9orf72 Repeat Expansion Disrupts Nucleocytoplasmic Transport

Overview

Journal Nature

Specialty Science

Date 2015 Aug 27

PMID 26308891

Citations 592

Authors

Ke Zhang

Christopher J Donnelly

Aaron R Haeusler

Jonathan C Grima

James B Machamer

Peter Steinwald

Elizabeth L Daley

Sean J Miller

Kathleen M Cunningham

Svetlana Vidensky

Saksham Gupta

Michael A Thomas

Ingie Hong

Shu-Ling Chiu

Richard L Huganir

Lyle W Ostrow

Michael J Matunis

Jiou Wang

Rita Sattler

Thomas E Lloyd

Jeffrey D Rothstein

Affiliations

Soon will be listed here.

Abstract

The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.

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