Dataset Information

Expression of ALS-linked mutant CCNF in zebrafish leads to increased cell death in the spinal cord and an aberrant motor phenotype

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. Approximately 10% of ALS cases have a known family history of the disease and mutations in multiple genes have been identified. ALS-linked mutations in CCNF were recently reported, however the pathogenic mechanisms associated with these mutations are yet to be established. To investigate possible mechanisms, an in vitro model of ALS was developed that expressed mutant CCNF in a neuronal cell line (Neuro-2a). Proteomic analysis of this in vitro model identified the disruption of several cellular pathways, including those associated with caspase-3 mediated cell death and axonal outgrowth. To establish whether these findings were replicated in vivo, a zebrafish model was developed. Transient overexpression of human mutant CCNF in zebrafish led to increased caspase-3 activity, increased cell death and a motor neuron axonopathy consisting of shortened primary motor axons and increased frequency of aberrant axonal branching. A significant correlation between the severity of this mutant CCNF-induced axonopathy and reduced motor function was also demonstrated in this model, with zebrafish expressing the mutant protein demonstrating an impaired motor response to a light stimulus. This is the first report of an ALS-linked CCNF mutation in vivo and indicates that zebrafish will be a useful tool to model the pathogenesis of CCNF-linked motor neuron degeneration.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Albert Lee

LAB HEAD: Dr. Albert Lee

PROVIDER: PXD005131 | Pride | 2017-05-22

REPOSITORIES: pride

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Expression of ALS/FTD-linked mutant CCNF in zebrafish leads to increased cell death in the spinal cord and an aberrant motor phenotype.

Hogan Alison L AL Don Emily K EK Rayner Stephanie L SL Lee Albert A Laird Angela S AS Watchon Maxinne M Winnick Claire C Tarr Ingrid S IS Morsch Marco M Fifita Jennifer A JA Gwee Serene S L SSL Formella Isabel I Hortle Elinor E Yuan Kristy C KC Molloy Mark P MP Williams Kelly L KL Nicholson Garth A GA Chung Roger S RS Blair Ian P IP Cole Nicholas J NJ

Human molecular genetics 20170701 14

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease characterised by the death of upper and lower motor neurons. Approximately 10% of cases have a known family history of ALS and disease-linked mutations in multiple genes have been identified. ALS-linked mutations in CCNF were recently reported, however the pathogenic mechanisms associated with these mutations are yet to be established. To investigate possible disease mechanisms, we developed in vitro an ...[more]

PMID: 28444311

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