Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice

Owen M. Peters; Gabriela Toro Cabrera; Helene Tran; Tania F. Gendron; Jeanne E. McKeon; Jake Metterville; Alexandra Weiss; Nicholas Wightman; Johnny Salameh; Juhyun Kim; Huaming Sun; Kevin B. Boylan; Dennis Dickson; Zachary Kennedy; Ziqiang Lin; Yong Jie Zhang; Lillian Daughrity; Chris Jung; Fen Biao Gao; Peter C. Sapp; H. Robert Horvitz; Daryl A. Bosco; Solange P. Brown; Pieter de Jong; Leonard Petrucelli; Christian Mueller; Robert H. Brown

doi:10.1016/j.neuron.2015.11.018

Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice

Owen M. Peters, Gabriela Toro Cabrera, Helene Tran, Tania F. Gendron, Jeanne E. McKeon, Jake Metterville, Alexandra Weiss, Nicholas Wightman, Johnny Salameh, Juhyun Kim, Huaming Sun, Kevin B. Boylan, Dennis Dickson, Zachary Kennedy, Ziqiang Lin, Yong Jie Zhang, Lillian Daughrity, Chris Jung, Fen Biao Gao, Peter C. SappH. Robert Horvitz, Daryl A. Bosco, Solange P. Brown, Pieter de Jong, Leonard Petrucelli, Christian Mueller, Robert H. Brown

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143 Scopus citations

Abstract

A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.

Original language	English (US)
Pages (from-to)	902-909
Number of pages	8
Journal	Neuron
Volume	88
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2015.11.018
State	Published - Dec 2 2015

Keywords

Amyotrophic lateral sclerosis (ALS)
C9ORF72
Frontotemporal dementia (FTD)
MicroRNA
Neurodegeneration
RAN translation
RNA foci
Repeat expansions
Transgenic mice

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2015.11.018

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Peters, O. M., Cabrera, G. T., Tran, H., Gendron, T. F., McKeon, J. E., Metterville, J., Weiss, A., Wightman, N., Salameh, J., Kim, J., Sun, H., Boylan, K. B., Dickson, D., Kennedy, Z., Lin, Z., Zhang, Y. J., Daughrity, L., Jung, C., Gao, F. B., ... Brown, R. H. (2015). Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice. Neuron, 88(5), 902-909. https://doi.org/10.1016/j.neuron.2015.11.018

Peters, OM, Cabrera, GT, Tran, H, Gendron, TF, McKeon, JE, Metterville, J, Weiss, A, Wightman, N, Salameh, J, Kim, J, Sun, H, Boylan, KB, Dickson, D, Kennedy, Z, Lin, Z, Zhang, YJ, Daughrity, L, Jung, C, Gao, FB, Sapp, PC, Horvitz, HR, Bosco, DA, Brown, SP, de Jong, P, Petrucelli, L, Mueller, C & Brown, RH 2015, 'Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice', Neuron, vol. 88, no. 5, pp. 902-909. https://doi.org/10.1016/j.neuron.2015.11.018

@article{210a9ef390e24305bfd0cd341f8e318e,

title = "Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice",

abstract = "A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.",

keywords = "Amyotrophic lateral sclerosis (ALS), C9ORF72, Frontotemporal dementia (FTD), MicroRNA, Neurodegeneration, RAN translation, RNA foci, Repeat expansions, Transgenic mice",

author = "Peters, {Owen M.} and Cabrera, {Gabriela Toro} and Helene Tran and Gendron, {Tania F.} and McKeon, {Jeanne E.} and Jake Metterville and Alexandra Weiss and Nicholas Wightman and Johnny Salameh and Juhyun Kim and Huaming Sun and Boylan, {Kevin B.} and Dennis Dickson and Zachary Kennedy and Ziqiang Lin and Zhang, {Yong Jie} and Lillian Daughrity and Chris Jung and Gao, {Fen Biao} and Sapp, {Peter C.} and Horvitz, {H. Robert} and Bosco, {Daryl A.} and Brown, {Solange P.} and {de Jong}, Pieter and Leonard Petrucelli and Christian Mueller and Brown, {Robert H.}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = dec,

day = "2",

doi = "10.1016/j.neuron.2015.11.018",

language = "English (US)",

volume = "88",

pages = "902--909",

journal = "Neuron",

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T1 - Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice

AU - Peters, Owen M.

AU - Cabrera, Gabriela Toro

AU - Tran, Helene

AU - Gendron, Tania F.

AU - McKeon, Jeanne E.

AU - Metterville, Jake

AU - Weiss, Alexandra

AU - Wightman, Nicholas

AU - Salameh, Johnny

AU - Kim, Juhyun

AU - Sun, Huaming

AU - Boylan, Kevin B.

AU - Dickson, Dennis

AU - Kennedy, Zachary

AU - Lin, Ziqiang

AU - Zhang, Yong Jie

AU - Daughrity, Lillian

AU - Jung, Chris

AU - Gao, Fen Biao

AU - Sapp, Peter C.

AU - Horvitz, H. Robert

AU - Bosco, Daryl A.

AU - Brown, Solange P.

AU - de Jong, Pieter

AU - Petrucelli, Leonard

AU - Mueller, Christian

AU - Brown, Robert H.

PY - 2015/12/2

Y1 - 2015/12/2

N2 - A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.

AB - A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.

KW - Amyotrophic lateral sclerosis (ALS)

KW - C9ORF72

KW - Frontotemporal dementia (FTD)

KW - MicroRNA

KW - Neurodegeneration

KW - RAN translation

KW - RNA foci

KW - Repeat expansions

KW - Transgenic mice

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DO - 10.1016/j.neuron.2015.11.018

M3 - Article

C2 - 26637797

AN - SCOPUS:84949445156

SN - 0896-6273

VL - 88

SP - 902

EP - 909

JO - Neuron

JF - Neuron

IS - 5

ER -

Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice

Abstract

Keywords

ASJC Scopus subject areas

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