C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

J.G. O'Rourke; L. Bogdanik; A.K.M.G. Muhammad; T.F. Gendron; K.J. Kim; A. Austin; J. Cady; E.Y. Liu; J. Zarrow; S. Grant; R. Ho; S. Bell; S. Carmona; M. Simpkinson; D. Lall; K. Wu; L. Daughrity; D.W. Dickson; M.B. Harms; L. Petrucelli; E.B. Lee; C.M. Lutz; R.H. Baloh

doi:10.1016/j.neuron.2015.10.027

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C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

Journal article

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C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

J.G. O'Rourke, L. Bogdanik, A.K.M.G. Muhammad, T.F. Gendron, K.J. Kim, A. Austin, J. Cady, E.Y. Liu, J. Zarrow, S. Grant, …

Neuron, Vol.88(5), pp.892-901

2015

DOI: https://doi.org/10.1016/j.neuron.2015.10.027

PMID: 26637796

Abstract

Age Factors

Amyotrophic Lateral Sclerosis

Animals

Brain

Cells, Cultured

Chromosomes, Artificial, Bacterial

Disease Models, Animal

DNA Repeat Expansion

Frontotemporal Dementia

Glutamic Acid

Humans

Mice

Mice, Transgenic

Motor Activity

Muscle Strength

Neuromuscular Junction

Neurons

Proteins

Psychomotor Performance

Spinal Cord

antisense oligonucleotide

dipeptide

nucleolin

repeat associated non ATG translated dipeptide

RNA

unclassified drug

C9orf72 protein, human

glutamic acid

protein

repetitive DNA

amyotrophic lateral sclerosis

animal cell

animal experiment

animal model

animal tissue

Article

bacterial artificial chromosome

behavior disorder

C9orf72 gene

cellular parameters

clinical feature

controlled study

cytopathology

DNA structure

frontotemporal dementia

gene targeting

genetic association

hexanucleotide repeat

male

mouse

nerve degeneration

neuropathology

nonhuman

nucleolar dysfunction

nucleolar stress

open reading frame

priority journal

skin fibroblast

transgenic mouse

age

amyotrophic lateral sclerosis

animal

bacterial artificial chromosome

brain

cell culture

disease model

drug effects

frontotemporal dementia

genetics

human

metabolism

motor activity

muscle strength

nerve cell

neuromuscular junction

pathology

pathophysiology

physiology

psychomotor performance

spinal cord

Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (∼100-1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients. © 2015 Elsevier Inc.

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Title: C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD
Creators: J.G. O'Rourke
L. Bogdanik - Jackson Laboratory
A.K.M.G. Muhammad - Cedars-Sinai Medical Center
T.F. Gendron - Mayo Clinic in Florida
K.J. Kim - Cedars-Sinai Medical Center
A. Austin - Jackson Laboratory
J. Cady - Washington University in St. Louis
E.Y. Liu - University of Pennsylvania
J. Zarrow - Cedars-Sinai Medical Center
S. Grant - Cedars-Sinai Medical Center
R. Ho - Cedars-Sinai Medical Center
S. Bell - Cedars-Sinai Medical Center
S. Carmona - Cedars-Sinai Medical Center
M. Simpkinson - Cedars-Sinai Medical Center
D. Lall - Cedars-Sinai Medical Center
K. Wu - Cedars-Sinai Medical Center
L. Daughrity - Mayo Clinic in Florida
D.W. Dickson - Mayo Clinic in Florida
M.B. Harms - Washington University in St. Louis
L. Petrucelli - Mayo Clinic in Florida
E.B. Lee - University of Pennsylvania
C.M. Lutz - Jackson Laboratory
R.H. Baloh - Cedars-Sinai Medical Center
Publication Details: Neuron, Vol.88(5), pp.892-901
Publisher: Cell Press; CAMBRIDGE
Number of pages: 10
Grant note: National Institutes of Health (NIH): NS055980, NS069669, G039510, AG000255, NS089979, NS084528, NS063964, NS077402, NS084974, ES20395 Department of Defense: ALSRP AL130125 Mayo Clinic FoundationMayo Clinic Center for Individualized MedicineALS AssociationRobert Packard Center for ALS Research at Johns HopkinsTarget ALSRobert and Louise Schwab FamilyCedars-Sinai ALS Research FundNational Center for Advancing Translational Sciences: UL1TR000124 National Institute on Aging: P01NS084974, T32AG000255
We would like to thank Uthra Rajamani and Dhruv Sareen for assistance with the ImageXpress, David Rushton and Virginia Mattis for assistance with the primary cortical cultures, Vince Funari for assistance with RNA-sequencing, and Frank Bennett and Frank Rigo of Isis Pharmaceuticals for supplying antisense oligonucleotides. This work was supported by National Institutes of Health (NIH) Grants NS055980 and NS069669 (R.H.B.), AG039510 (E.B.L.), AG000255 (E.Y.L.), NS089979 (T.F.G.), NS084528 (L.P.), NS063964 (L.P.), NS077402 (L.P.), NS084974 (L.P.), and ES20395 (L.P.); Department of Defense ALSRP AL130125 (L.P.); the Mayo Clinic Foundation (L.P.); Mayo Clinic Center for Individualized Medicine (L.P.); ALS Association (L.P., T.F.G.); Robert Packard Center for ALS Research at Johns Hopkins (L.P.); Target ALS (L.P., R.H.B.); the Robert and Louise Schwab Family (R.H.B.); and the Cedars-Sinai ALS Research Fund (R.H.B.). The project was supported by the National Center for Advancing Translational Sciences, Grant UL1TR000124.
Comment: Export Date: 27 February 2026; Cited By: 235; CODEN: NERNE
Academic Unit: Level 02 - Executives; Executives; UMMG Department of Neurology
Resource Type: Journal article
PMID: 26637796
Record Identifier: 991032995736302976