Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration

Peter I. Joyce; Pietro Fratta; Allison S. Landman; Philip Mcgoldrick; Henning Wackerhage; Michael Groves; Bharani Shiva Busam; Jorge Galino; Silvia Corrochano; Olga A. Beskina; Christopher Esapa; Edward Ryder; Sarah Carter; Michelle Stewart; Gemma Codner; Helen Hilton; Lydia Teboul; Jennifer Tucker; Arimantas Lionikas; Jeanne Estabel; Ramiro Ramirez-Solis; Jacqueline K. White; Sebastian Brandner; Vincent Plagnol; David L. H. Bennet; Andrey Y. Abramov; Linda Greensmith; Elizabeth M. C. Fisher; Abraham Acevedo-Arozena

doi:10.1093/hmg/ddv471

Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration

Peter I. Joyce, Pietro Fratta, Allison S. Landman, Philip Mcgoldrick, Henning Wackerhage, Michael Groves, Bharani Shiva Busam, Jorge Galino, Silvia Corrochano, Olga A. Beskina, Christopher Esapa, Edward Ryder, Sarah Carter, Michelle Stewart, Gemma Codner, Helen Hilton, Lydia Teboul, Jennifer Tucker, Arimantas Lionikas, Jeanne EstabelRamiro Ramirez-Solis, Jacqueline K. White, Sebastian Brandner, Vincent Plagnol, David L. H. Bennet, Andrey Y. Abramov, Linda Greensmith, Elizabeth M. C. Fisher, Abraham Acevedo-Arozena

Medical Sciences

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Abstract

Zinc finger motifs are distributed amongst many eukaryotic protein families, directing nucleic acid-protein and protein-protein interactions. Zinc finger protein 106 (ZFP106) has previously been associated with roles in immune response, muscle differentiation, testes development and DNA damage, although little is known about its specific function. To further investigate the function of ZFP106, we performed an in-depth characterization of Zfp106 deficient mice (Zfp106(-/-)), and we report a novel role for ZFP106 in motor and sensory neuronal maintenance and survival. Zfp106(-/-) mice develop severe motor abnormalities, major deficits in muscle strength and histopathological changes in muscle. Intriguingly, despite being highly expressed throughout the central nervous system, Zfp106(-/-) mice undergo selective motor and sensory neuronal and axonal degeneration specific to the spinal cord and peripheral nervous system. Neurodegeneration does not occur during development of Zfp106(-/-) mice, suggesting that ZFP106 is likely required for the maintenance of mature peripheral motor and sensory neurons. Analysis of embryonic Zfp106(-/-) motor neurons revealed deficits in mitochondrial function, with an inhibition of Complex I within the mitochondrial electron transport chain. Our results highlight a vital role for ZFP106 in sensory and motor neuron maintenance and reveal a novel player in mitochondrial dysfunction and neurodegeneration.

Original language	English
Pages (from-to)	291-307
Number of pages	17
Journal	Human Molecular Genetics
Volume	25
Issue number	2
Early online date	24 Nov 2015
DOIs	https://doi.org/10.1093/hmg/ddv471
Publication status	Published - 15 Jan 2016

Bibliographical note

Acknowledgements
We are indebted to Jim Humphries, JennyCorrigan, LizDarley, Elizabeth Joynson, Natalie Walters, Sara Wells and the whole necropsy, histology, genotyping and MLC ward 6 teams at MRC Harwell for excellent technical assistance. We thank the staff of the WTSI Illumina Bespoke Team for the RNA-seq data, the Sanger Mouse Genetics Project for the initial mouse characterization and Dr David Adams for critical reading of the manuscript. We also thank KOMP for the mouse embryonic stem cells carrying the knockout first promoter-less allele (tm1a(KOMP)Wtsi) within Zfp016.

Conflict of Interest statement. None declared.

Funding This work was funded by the UK Medical Research Council (MRC) to A.A.-A. and a Motor Neurone Disease Association (MNDA) project grant to A.A.-A. and EMCF. D.L.H.B. is a Wellcome Trust Senior Clinical Scientist Fellow and P.F. is a MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellow. Funding to pay the Open Access publication charges for this article was provided by the MRC grant number: MC_UP_A390_1106.

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Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration
© The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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Joyce, P. I., Fratta, P., Landman, A. S., Mcgoldrick, P., Wackerhage, H., Groves, M., Busam, B. S., Galino, J., Corrochano, S., Beskina, O. A., Esapa, C., Ryder, E., Carter, S., Stewart, M., Codner, G., Hilton, H., Teboul, L., Tucker, J., Lionikas, A., ... Acevedo-Arozena, A. (2016). Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration. Human Molecular Genetics, 25(2), 291-307. https://doi.org/10.1093/hmg/ddv471

Joyce, PI, Fratta, P, Landman, AS, Mcgoldrick, P, Wackerhage, H, Groves, M, Busam, BS, Galino, J, Corrochano, S, Beskina, OA, Esapa, C, Ryder, E, Carter, S, Stewart, M, Codner, G, Hilton, H, Teboul, L, Tucker, J, Lionikas, A, Estabel, J, Ramirez-Solis, R, White, JK, Brandner, S, Plagnol, V, Bennet, DLH, Abramov, AY, Greensmith, L, Fisher, EMC & Acevedo-Arozena, A 2016, 'Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration', Human Molecular Genetics, vol. 25, no. 2, pp. 291-307. https://doi.org/10.1093/hmg/ddv471

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title = "Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration",

abstract = "Zinc finger motifs are distributed amongst many eukaryotic protein families, directing nucleic acid-protein and protein-protein interactions. Zinc finger protein 106 (ZFP106) has previously been associated with roles in immune response, muscle differentiation, testes development and DNA damage, although little is known about its specific function. To further investigate the function of ZFP106, we performed an in-depth characterization of Zfp106 deficient mice (Zfp106(-/-)), and we report a novel role for ZFP106 in motor and sensory neuronal maintenance and survival. Zfp106(-/-) mice develop severe motor abnormalities, major deficits in muscle strength and histopathological changes in muscle. Intriguingly, despite being highly expressed throughout the central nervous system, Zfp106(-/-) mice undergo selective motor and sensory neuronal and axonal degeneration specific to the spinal cord and peripheral nervous system. Neurodegeneration does not occur during development of Zfp106(-/-) mice, suggesting that ZFP106 is likely required for the maintenance of mature peripheral motor and sensory neurons. Analysis of embryonic Zfp106(-/-) motor neurons revealed deficits in mitochondrial function, with an inhibition of Complex I within the mitochondrial electron transport chain. Our results highlight a vital role for ZFP106 in sensory and motor neuron maintenance and reveal a novel player in mitochondrial dysfunction and neurodegeneration.",

author = "Joyce, {Peter I.} and Pietro Fratta and Landman, {Allison S.} and Philip Mcgoldrick and Henning Wackerhage and Michael Groves and Busam, {Bharani Shiva} and Jorge Galino and Silvia Corrochano and Beskina, {Olga A.} and Christopher Esapa and Edward Ryder and Sarah Carter and Michelle Stewart and Gemma Codner and Helen Hilton and Lydia Teboul and Jennifer Tucker and Arimantas Lionikas and Jeanne Estabel and Ramiro Ramirez-Solis and White, {Jacqueline K.} and Sebastian Brandner and Vincent Plagnol and Bennet, {David L. H.} and Abramov, {Andrey Y.} and Linda Greensmith and Fisher, {Elizabeth M. C.} and Abraham Acevedo-Arozena",

note = "Acknowledgements We are indebted to Jim Humphries, JennyCorrigan, LizDarley, Elizabeth Joynson, Natalie Walters, Sara Wells and the whole necropsy, histology, genotyping and MLC ward 6 teams at MRC Harwell for excellent technical assistance. We thank the staff of the WTSI Illumina Bespoke Team for the RNA-seq data, the Sanger Mouse Genetics Project for the initial mouse characterization and Dr David Adams for critical reading of the manuscript. We also thank KOMP for the mouse embryonic stem cells carrying the knockout first promoter-less allele (tm1a(KOMP)Wtsi) within Zfp016. Conflict of Interest statement. None declared. Funding This work was funded by the UK Medical Research Council (MRC) to A.A.-A. and a Motor Neurone Disease Association (MNDA) project grant to A.A.-A. and EMCF. D.L.H.B. is a Wellcome Trust Senior Clinical Scientist Fellow and P.F. is a MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellow. Funding to pay the Open Access publication charges for this article was provided by the MRC grant number: MC_UP_A390_1106.",

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doi = "10.1093/hmg/ddv471",

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T1 - Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration

AU - Joyce, Peter I.

AU - Fratta, Pietro

AU - Landman, Allison S.

AU - Mcgoldrick, Philip

AU - Wackerhage, Henning

AU - Groves, Michael

AU - Busam, Bharani Shiva

AU - Galino, Jorge

AU - Corrochano, Silvia

AU - Beskina, Olga A.

AU - Esapa, Christopher

AU - Ryder, Edward

AU - Carter, Sarah

AU - Stewart, Michelle

AU - Codner, Gemma

AU - Hilton, Helen

AU - Teboul, Lydia

AU - Tucker, Jennifer

AU - Lionikas, Arimantas

AU - Estabel, Jeanne

AU - Ramirez-Solis, Ramiro

AU - White, Jacqueline K.

AU - Brandner, Sebastian

AU - Plagnol, Vincent

AU - Bennet, David L. H.

AU - Abramov, Andrey Y.

AU - Greensmith, Linda

AU - Fisher, Elizabeth M. C.

AU - Acevedo-Arozena, Abraham

N1 - Acknowledgements We are indebted to Jim Humphries, JennyCorrigan, LizDarley, Elizabeth Joynson, Natalie Walters, Sara Wells and the whole necropsy, histology, genotyping and MLC ward 6 teams at MRC Harwell for excellent technical assistance. We thank the staff of the WTSI Illumina Bespoke Team for the RNA-seq data, the Sanger Mouse Genetics Project for the initial mouse characterization and Dr David Adams for critical reading of the manuscript. We also thank KOMP for the mouse embryonic stem cells carrying the knockout first promoter-less allele (tm1a(KOMP)Wtsi) within Zfp016. Conflict of Interest statement. None declared. Funding This work was funded by the UK Medical Research Council (MRC) to A.A.-A. and a Motor Neurone Disease Association (MNDA) project grant to A.A.-A. and EMCF. D.L.H.B. is a Wellcome Trust Senior Clinical Scientist Fellow and P.F. is a MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellow. Funding to pay the Open Access publication charges for this article was provided by the MRC grant number: MC_UP_A390_1106.

PY - 2016/1/15

Y1 - 2016/1/15

N2 - Zinc finger motifs are distributed amongst many eukaryotic protein families, directing nucleic acid-protein and protein-protein interactions. Zinc finger protein 106 (ZFP106) has previously been associated with roles in immune response, muscle differentiation, testes development and DNA damage, although little is known about its specific function. To further investigate the function of ZFP106, we performed an in-depth characterization of Zfp106 deficient mice (Zfp106(-/-)), and we report a novel role for ZFP106 in motor and sensory neuronal maintenance and survival. Zfp106(-/-) mice develop severe motor abnormalities, major deficits in muscle strength and histopathological changes in muscle. Intriguingly, despite being highly expressed throughout the central nervous system, Zfp106(-/-) mice undergo selective motor and sensory neuronal and axonal degeneration specific to the spinal cord and peripheral nervous system. Neurodegeneration does not occur during development of Zfp106(-/-) mice, suggesting that ZFP106 is likely required for the maintenance of mature peripheral motor and sensory neurons. Analysis of embryonic Zfp106(-/-) motor neurons revealed deficits in mitochondrial function, with an inhibition of Complex I within the mitochondrial electron transport chain. Our results highlight a vital role for ZFP106 in sensory and motor neuron maintenance and reveal a novel player in mitochondrial dysfunction and neurodegeneration.

AB - Zinc finger motifs are distributed amongst many eukaryotic protein families, directing nucleic acid-protein and protein-protein interactions. Zinc finger protein 106 (ZFP106) has previously been associated with roles in immune response, muscle differentiation, testes development and DNA damage, although little is known about its specific function. To further investigate the function of ZFP106, we performed an in-depth characterization of Zfp106 deficient mice (Zfp106(-/-)), and we report a novel role for ZFP106 in motor and sensory neuronal maintenance and survival. Zfp106(-/-) mice develop severe motor abnormalities, major deficits in muscle strength and histopathological changes in muscle. Intriguingly, despite being highly expressed throughout the central nervous system, Zfp106(-/-) mice undergo selective motor and sensory neuronal and axonal degeneration specific to the spinal cord and peripheral nervous system. Neurodegeneration does not occur during development of Zfp106(-/-) mice, suggesting that ZFP106 is likely required for the maintenance of mature peripheral motor and sensory neurons. Analysis of embryonic Zfp106(-/-) motor neurons revealed deficits in mitochondrial function, with an inhibition of Complex I within the mitochondrial electron transport chain. Our results highlight a vital role for ZFP106 in sensory and motor neuron maintenance and reveal a novel player in mitochondrial dysfunction and neurodegeneration.

U2 - 10.1093/hmg/ddv471

DO - 10.1093/hmg/ddv471

M3 - Article

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VL - 25

SP - 291

EP - 307

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 2

ER -

Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration

Abstract

Bibliographical note

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