Absence of Survival and Motor Deficits in 500 Repeat C9ORF72 BAC Mice

Daniel A Mordes; Brett M Morrison; Xanthe H Ament; Christopher Cantrell; Joanie Mok; Pierce Eggan; Carolyn Xue; Jin-Yuan Wang; Kevin Eggan; Jeffrey D Rothstein

doi:10.1016/j.neuron.2020.08.009

Absence of Survival and Motor Deficits in 500 Repeat C9ORF72 BAC Mice

Neuron. 2020 Nov 25;108(4):775-783.e4. doi: 10.1016/j.neuron.2020.08.009. Epub 2020 Oct 5.

Authors

Affiliations

¹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
² Department of Neurology, The Johns Hopkins University, Baltimore, MD 21205, USA.
³ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: eggan@mcb.harvard.edu.
⁵ Department of Neurology, The Johns Hopkins University, Baltimore, MD 21205, USA; Brain Science Institute, The Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: jrothstein@jhmi.edu.

PMID: 33022228
DOI: 10.1016/j.neuron.2020.08.009

Abstract

A hexanucleotide repeat expansion at C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Initial studies of bacterial artificial chromosome (BAC) transgenic mice harboring this expansion described an absence of motor and survival phenotypes. However, a recent study by Liu and colleagues described transgenic mice harboring a large repeat expansion (C9-500) and reported decreased survival and progressive motor phenotypes. To determine the utility of the C9-500 animals for understanding degenerative mechanisms, we validated and established two independent colonies of transgene carriers. However, extended studies of these animals for up to 1 year revealed no reproducible abnormalities in survival, motor function, or neurodegeneration. Here, we propose several potential explanations for the disparate nature of our findings from those of Liu and colleagues. Resolving the discrepancies we identify will be essential to settle the translational utility of C9-500 mice. This Matters Arising paper is in response to Liu et al. (2016), published in Neuron. See also the response by Nguyen et al. (2020), published in this issue.

Keywords: ALS; C9orf72; FTD; RAN translation; mouse model; neurodegeneration.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / physiopathology*
Animals
C9orf72 Protein / genetics
C9orf72 Protein / physiology*
DNA Repeat Expansion / genetics
Disease Models, Animal
Heterozygote
Male
Mice
Mice, Transgenic
Motor Skills / physiology*
Nerve Degeneration / physiopathology*
Phenotype
Survival / physiology*

Substances

C9orf72 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding