C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits

Jeannie Chew; Tania F. Gendron; Mercedes Prudencio; Hiroki Sasaguri; Yong Jie Zhang; Monica Castanedes-Casey; Chris W. Lee; Karen Jansen-West; Aishe Kurti; Melissa E. Murray; Kevin F. Bieniek; Peter O. Bauer; Ena C. Whitelaw; Linda Rousseau; Jeannette N. Stankowski; Caroline Stetler; Lillian M. Daughrity; Emilie A. Perkerson; Pamela Desaro; Amelia Johnston; Karen Overstreet; Dieter Edbauer; Rosa Rademakers; Kevin B. Boylan; Dennis W. Dickson; John D. Fryer; Leonard Petrucelli

doi:10.1126/science.aaa9344

C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits

Jeannie Chew, Tania F. Gendron, Mercedes Prudencio, Hiroki Sasaguri, Yong Jie Zhang, Monica Castanedes-Casey, Chris W. Lee, Karen Jansen-West, Aishe Kurti, Melissa E. Murray, Kevin F. Bieniek, Peter O. Bauer, Ena C. Whitelaw, Linda Rousseau, Jeannette N. Stankowski, Caroline Stetler, Lillian M. Daughrity, Emilie A. Perkerson, Pamela Desaro, Amelia JohnstonKaren Overstreet, Dieter Edbauer, Rosa Rademakers, Kevin B. Boylan, Dennis W. Dickson, John D. Fryer, Leonard Petrucelli

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Abstract

The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G₄C₂ repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G₄C₂)₆₆ throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G₄C₂)₆₆ mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.

Original language	English (US)
Pages (from-to)	1151-1154
Number of pages	4
Journal	Science
Volume	348
Issue number	6239
DOIs	https://doi.org/10.1126/science.aaa9344
State	Published - Jun 5 2015

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Chew, J., Gendron, T. F., Prudencio, M., Sasaguri, H., Zhang, Y. J., Castanedes-Casey, M., Lee, C. W., Jansen-West, K., Kurti, A., Murray, M. E., Bieniek, K. F., Bauer, P. O., Whitelaw, E. C., Rousseau, L., Stankowski, J. N., Stetler, C., Daughrity, L. M., Perkerson, E. A., Desaro, P., ... Petrucelli, L. (2015). C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science, 348(6239), 1151-1154. https://doi.org/10.1126/science.aaa9344

Chew, J, Gendron, TF , Prudencio, M, Sasaguri, H, Zhang, YJ, Castanedes-Casey, M, Lee, CW, Jansen-West, K, Kurti, A, Murray, ME, Bieniek, KF, Bauer, PO, Whitelaw, EC, Rousseau, L, Stankowski, JN, Stetler, C, Daughrity, LM, Perkerson, EA, Desaro, P, Johnston, A, Overstreet, K, Edbauer, D, Rademakers, R, Boylan, KB, Dickson, DW, Fryer, JD & Petrucelli, L 2015, 'C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits', Science, vol. 348, no. 6239, pp. 1151-1154. https://doi.org/10.1126/science.aaa9344

@article{fc14f098e17b4d6888b1aa245120bb24,

title = "C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits",

abstract = "The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with {"}c9FTD/ALS{"} are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.",

author = "Jeannie Chew and Gendron, {Tania F.} and Mercedes Prudencio and Hiroki Sasaguri and Zhang, {Yong Jie} and Monica Castanedes-Casey and Lee, {Chris W.} and Karen Jansen-West and Aishe Kurti and Murray, {Melissa E.} and Bieniek, {Kevin F.} and Bauer, {Peter O.} and Whitelaw, {Ena C.} and Linda Rousseau and Stankowski, {Jeannette N.} and Caroline Stetler and Daughrity, {Lillian M.} and Perkerson, {Emilie A.} and Pamela Desaro and Amelia Johnston and Karen Overstreet and Dieter Edbauer and Rosa Rademakers and Boylan, {Kevin B.} and Dickson, {Dennis W.} and Fryer, {John D.} and Leonard Petrucelli",

year = "2015",

month = jun,

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doi = "10.1126/science.aaa9344",

language = "English (US)",

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AU - Chew, Jeannie

AU - Gendron, Tania F.

AU - Prudencio, Mercedes

AU - Sasaguri, Hiroki

AU - Zhang, Yong Jie

AU - Castanedes-Casey, Monica

AU - Lee, Chris W.

AU - Jansen-West, Karen

AU - Kurti, Aishe

AU - Murray, Melissa E.

AU - Bieniek, Kevin F.

AU - Bauer, Peter O.

AU - Whitelaw, Ena C.

AU - Rousseau, Linda

AU - Stankowski, Jeannette N.

AU - Stetler, Caroline

AU - Daughrity, Lillian M.

AU - Perkerson, Emilie A.

AU - Desaro, Pamela

AU - Johnston, Amelia

AU - Overstreet, Karen

AU - Edbauer, Dieter

AU - Rademakers, Rosa

AU - Boylan, Kevin B.

AU - Dickson, Dennis W.

AU - Fryer, John D.

AU - Petrucelli, Leonard

PY - 2015/6/5

Y1 - 2015/6/5

N2 - The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.

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C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits

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