Published in

Nature Research, Nature Communications, 1(7), 2016

DOI: 10.1038/ncomms11253

Links

Tools

Export citation

Search in Google Scholar

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Journal article published in 2016 by Kelly L. Williams ORCID, Simon Topp ORCID, Shu Yang, Bradley Smith, Jennifer A. Fifita, Sadaf T. Warraich, Katharine Y. Zhang, Natalie Farrawell, Marka van Blitterswijk, Caroline Vance ORCID, Xun Hu, Alessandra Chesi, Claire S. Leblond, Albert Lee ORCID, Stephanie L. Rayner and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

Full text: Download

Green circle
Preprint: archiving allowed
Upload
Red circle
Postprint: archiving forbidden
Green circle
Published version: archiving allowed
Upload
Policy details
Data provided by SHERPA/RoMEO

Abstract

AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase complex (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.