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

Hogan, AL; Don, EK; Rayner, SL; Lee, A; Laird, AS; Watchon, M; Winnick, C; Tarr, IS; Morsch, M; Fifita, JA; Gwee, SSL; Formella, I; Hortle, E; Yuan, KC; Molloy, MP; Williams, KL; Nicholson, GA; Chung, RS; Blair, IP; Cole, NJ

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

Hogan, AL Don, EK Rayner, SL Lee, A Laird, AS Watchon, M Winnick, C Tarr, IS Morsch, M Fifita, JA Gwee, SSL Formella, I Hortle, E

Yuan, KC Molloy, MP Williams, KL Nicholson, GA Chung, RS Blair, IP Cole, NJ

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Publisher:: Oxford University Press
Publication Type:: Journal Article
Citation:: Human Molecular Genetics, 2017, 26, (14), pp. 2616-2626
Issue Date:: 2017-07-15

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Field	Value	Language
dc.contributor.author	Hogan, AL
dc.contributor.author	Don, EK
dc.contributor.author	Rayner, SL
dc.contributor.author	Lee, A
dc.contributor.author	Laird, AS
dc.contributor.author	Watchon, M
dc.contributor.author	Winnick, C
dc.contributor.author	Tarr, IS
dc.contributor.author	Morsch, M
dc.contributor.author	Fifita, JA
dc.contributor.author	Gwee, SSL
dc.contributor.author	Formella, I
dc.contributor.author	Hortle, E https://orcid.org/0000-0001-9633-5638
dc.contributor.author	Yuan, KC
dc.contributor.author	Molloy, MP
dc.contributor.author	Williams, KL
dc.contributor.author	Nicholson, GA
dc.contributor.author	Chung, RS
dc.contributor.author	Blair, IP
dc.contributor.author	Cole, NJ
dc.date.accessioned	2022-09-02T05:21:42Z
dc.date.available	2017-03-29
dc.date.available	2022-09-02T05:21:42Z
dc.date.issued	2017-07-15
dc.identifier.citation	Human Molecular Genetics, 2017, 26, (14), pp. 2616-2626
dc.identifier.issn	0964-6906
dc.identifier.issn	1460-2083
dc.identifier.uri	http://hdl.handle.net/10453/161220
dc.description.abstract	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 and in vivo models based on an ALS-linked missense mutation in CCNF. Proteomic analysis of the in vitro models identified the disruption of several cellular pathways in the mutant model, including caspase-3 mediated cell death. Transient overexpression of human CCNF in zebrafish embryos supported this finding, with fish expressing the mutant protein found to have increased levels of cleaved (activated) caspase-3 and increased cell death in the spinal cord. The mutant CCNF fish also developed a motor neuron axonopathy consisting of shortened primary motor axons and increased frequency of aberrant axonal branching. Importantly, we demonstrated a significant correlation between the severity of the CCNF-induced axonopathy and a reduced motor response to a light stimulus (photomotor response). This is the first report of an ALS-linked CCNF mutation in vivo and taken together with the in vitro model identifies the disruption of cell death pathways as a significant consequence of this mutation. Additionally, this study presents a valuable new tool for use in ongoing studies investigating the pathobiology of ALS-linked CCNF mutations.
dc.format	Print
dc.language	eng
dc.publisher	Oxford University Press
dc.relation.ispartof	Human Molecular Genetics
dc.relation.isbasedon	10.1093/hmg/ddx136
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	06 Biological Sciences, 11 Medical and Health Sciences
dc.subject.classification	Genetics & Heredity
dc.subject.mesh	Amyotrophic Lateral Sclerosis
dc.subject.mesh	Animals
dc.subject.mesh	Animals, Genetically Modified
dc.subject.mesh	Axons
dc.subject.mesh	Caspase 3
dc.subject.mesh	Cell Death
dc.subject.mesh	Cyclins
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Frontotemporal Dementia
dc.subject.mesh	Humans
dc.subject.mesh	Motor Neurons
dc.subject.mesh	Mutation, Missense
dc.subject.mesh	Spinal Cord
dc.subject.mesh	Superoxide Dismutase
dc.subject.mesh	Zebrafish
dc.subject.mesh	Amyotrophic Lateral Sclerosis
dc.subject.mesh	Animals
dc.subject.mesh	Animals, Genetically Modified
dc.subject.mesh	Axons
dc.subject.mesh	Caspase 3
dc.subject.mesh	Cell Death
dc.subject.mesh	Cyclins
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Frontotemporal Dementia
dc.subject.mesh	Humans
dc.subject.mesh	Motor Neurons
dc.subject.mesh	Mutation, Missense
dc.subject.mesh	Spinal Cord
dc.subject.mesh	Superoxide Dismutase
dc.subject.mesh	Zebrafish
dc.subject.mesh	Spinal Cord
dc.subject.mesh	Axons
dc.subject.mesh	Motor Neurons
dc.subject.mesh	Animals
dc.subject.mesh	Animals, Genetically Modified
dc.subject.mesh	Zebrafish
dc.subject.mesh	Humans
dc.subject.mesh	Amyotrophic Lateral Sclerosis
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Superoxide Dismutase
dc.subject.mesh	Cyclins
dc.subject.mesh	Cell Death
dc.subject.mesh	Mutation, Missense
dc.subject.mesh	Caspase 3
dc.subject.mesh	Frontotemporal Dementia
dc.title	Expression of ALS/FTD-linked mutant CCNF in zebrafish leads to increased cell death in the spinal cord and an aberrant motor phenotype.
dc.type	Journal Article
utslib.citation.volume	26
utslib.location.activity	England
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-09-02T05:21:41Z
pubs.issue	14
pubs.publication-status	Published
pubs.volume	26
utslib.citation.issue	14

Abstract:

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 and in vivo models based on an ALS-linked missense mutation in CCNF. Proteomic analysis of the in vitro models identified the disruption of several cellular pathways in the mutant model, including caspase-3 mediated cell death. Transient overexpression of human CCNF in zebrafish embryos supported this finding, with fish expressing the mutant protein found to have increased levels of cleaved (activated) caspase-3 and increased cell death in the spinal cord. The mutant CCNF fish also developed a motor neuron axonopathy consisting of shortened primary motor axons and increased frequency of aberrant axonal branching. Importantly, we demonstrated a significant correlation between the severity of the CCNF-induced axonopathy and a reduced motor response to a light stimulus (photomotor response). This is the first report of an ALS-linked CCNF mutation in vivo and taken together with the in vitro model identifies the disruption of cell death pathways as a significant consequence of this mutation. Additionally, this study presents a valuable new tool for use in ongoing studies investigating the pathobiology of ALS-linked CCNF mutations.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/161220