CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia
File(s)
Published version
Author(s)
de Belleroche, JS
Type
Journal Article
Abstract
Amyotrophic 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.
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.
Date Issued
2016-04-15
Date Acceptance
2016-03-07
Citation
Nature Communications, 2016, 7
ISSN
2041-1723
Publisher
Nature Publishing Group
Journal / Book Title
Nature Communications
Volume
7
Copyright Statement
This work is licensed under a Creative Commons Attribution 4.0
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article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
License URL
Sponsor
Medical Research Council (MRC)
Grant Number
G0900688
Subjects
MD Multidisciplinary
Publication Status
Published
Article Number
11253