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 Johnston

Karen Overstreet, Dieter Edbauer, Rosa Rademakers, Kevin B. Boylan, Dennis W. Dickson, John D. Fryer, Leonard Petrucelli

Research output: Contribution to journal › Article › peer-review

320 Scopus citations

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
Externally published	Yes

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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{6fc086cb3a654820b8227fe331ad7c35,

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.

AB - 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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JO - Science

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

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