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Title
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CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Nature communications
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Publication
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2016
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ISSN
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2041-1723
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DOI
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10.1038/NCOMMS11253
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Volume/pages
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7
(2016)
, 8 p.
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Article Reference
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11253
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ISI
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000374125800001
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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