research highlights

EXPERIMENTAL MODEL Modeling ALS/FTD in mice: Updates on the C9orf72 BAC transgenic mice Mordes, D.A. et al 108, 775–783.e4 (2020) Nguyen, L. et al. Neuron 108, 784–796.e3 (2020)

Amyotrophic lateral sclerosis (ALS) is a shown by Liu et al. could be reproduced neurodegenerative disease characterized by in four different cohorts of FVB C9-500 a progressive loss of motor , which BAC transgenic mice, including two new leads to muscle weakness and eventual studies performed independently at the paralysis and respiratory failure. University of Bern and the University of in the C9orf72 have been identified Rochester Medical Center. In a previous as the major cause of ALS, accounting for report, Nguyen et al. had also shown that 40–50% of familial ALS cases and ~7% the phenotype of C9-500 mice including of sporadic cases. The mutations, which decreased survival, DigiGait abnormalities, consist of hexanucleotide repeat expansions open field abnormalities, loss, (GGGGCC) have also been linked to RNA foci and RAN accumulation (FTD). could be improved by targeting GA RAN The high prevalence of these mutations with a-GA1 antibody, which in ALS and FTD has led to the development would further support that the FVB C9-500 of several mouse models, including several phenotype is caused by RAN protein bacterial artificial (BAC) pathology and not a FVB-strain phenotype. transgenic mice, harboring GGGGCC Credit: Marina Spence/ Springer Nature “Although occasional seizures occurred repeat expansions. Most BAC transgenic in NT FVB mice, as reported in the initial models have pathological features of study by Liu et al. (2016), the presence of ALS/FTD, including accumulation in the seizures did not interfere with detection of CNS of repeat RNAs and dipeptide repeat to those reported by Liu and colleagues clear phenotypic differences in behavior, proteins created via repeat-associated is that housing environment somehow neuropathology, and survival between non-AUG (RAN) translation of repeat RNA. contributes to phenotypic manifestations C9-BAC mice and their NT littermates,” However, to date, very few models such as in C9-500 animals,” write the investigators. explain Nguyen et al. They propose that the C9-500 transgenic mice—a C9orf72 BAC This hypothesis is based on previous studies small number of control NT animals used mouse model with ~500 repeats developed that have shown that vivarium-dependent by Mordes et al. might explain the absence by Liu et al. at the University of Florida— commensal micro-organisms can affect of significant differences in survival between have shown reduced survival and signs the severity of symptoms in other mouse C9-500 transgenic and NT littermates, of motor deficits and . models of ALS. and that methodological differences might C9-500 transgenic mice could be valuable The second explanation proposed by account for weight loss, grip strength, and to study C9orf72 pathogenesis but a new Mordes et al. is that the genetic background open field discrepancies between studies. paper calls for caution when interpreting the of the mice might have compromised the Further investigations are needed to phenotype of these mice. analysis. C9-500 transgenic animals have identify the genetic and/or environmental In Neuron, Mordes et al. publish a been generated and studied on a FVB/N factors responsible for the differences in Matter Arising article as a response to the genetic background, which has been phenotype observed in C9-BAC mice across study by Liu et al. They report that two associated with a syndrome of sudden death laboratories. Determining whether the independent colonies of C9-500 transgenic and variable CNS lesions named space cadet C9orf72 transgene is sufficient to trigger mice phenotyped at Harvard University syndrome (SCS). Mordes et al. suggest that disease-associated phenotypes in mice is an and Johns Hopkins University did not show FVB C9-500 animals in the Liu et al. study important step towards our understanding abnormalities in survival, motor function might have developed more signs of SCS by of C9orf72 ALS/FTD pathogenesis. or neurodegeneration. The team provides chance than non-transgenic (NT) FVB mice. two possible explanations for the phenotypic In the same issue of Neuron, Nguyen Alexandra Le Bras differences between their study and the et al. from the University of Florida reply to work by Liu. et al. “One explanation for the the Matter Arising article by emphasizing Published online: 18 December 2020 disparate nature of our findings relative that the survival and motor phenotypes https://doi.org/10.1038/s41684-020-00693-9

Lab AnImal | VOL 50 | January 2021 | 13–18 | www.nature.com/laban 13