Xiang X, Piers TM, Wefers B, Zhu K, Mallach A, Brunner B, Kleinberger G, Song W, Colonna M, Herms J, Wurst W, Pocock JM, Haass C. The Trem2 R47H Alzheimer's risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans. Mol Neurodegener. 2018 Sep 6;13(1):49. PubMed.

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- Bruce Lamb
  Indiana University
- Posted: 13 Sep 2018
- News: Model Morass? R47H Mutation Scuttles TREM2 Expression in Mice, Not People
Xiang et al. report altered splicing of mouse TREM2 that is dependent upon the presence of the R47H mutation that was introduced into mice by three different groups (Christian Haas and colleagues, Bruce Lamb/Gary Landreth, and the MODEL-AD Consortium). Using whole-brain transcriptomics, we have confirmed an alteration in splicing in both the Lamb/Landreth and MODEL-AD R47H mice at multiple ages up to 12 months that involves a novel splice site and removal of 119 base pairs of the coding sequence of TREM2. Frances Edwards from the Dementia Research Institute, London, who kindly shared her analysis of the MODEL-AD R47H mice, has reported the same splicing. The alternative isoform is generated at 10 percent of the levels of full-length TREM2, likely due to nonsense-mediated decay. Given that all three R47H TREM2 mouse strains contain slightly different silent mutations induced as part of CRISPR targeting, it seems likely that the alternative splicing is due primarily to the R47H allele.

Xiang and colleagues report that the human R47H TREM2 variant is not spliced in this fashion, and we also have not observed altered splicing of human TREM2 via transcriptomic analysis of brain RNA from an R47H carrier. Importantly, however, in both the Lamb/Landreth and MODEL-AD homozygous R47H knock-in mouse strains it appears that full-length Trem2 transcripts are still expressed at ~50 percent of wild-type levels based upon RNA-seq analysis. Therefore, it is surprising and intriguing that Xiang et al. observe almost no detectable protein in microglia homozygous for R47H TREM2.

We are currently performing analyses of brain protein levels of TREM2 to determine if brain TREM2 protein expression is similarly reduced in the Lamb/Landreth and MODEL-AD R47H models. Furthermore, we are also performing whole-brain transcriptomic analysis comparing heterozygous and homozygous Trem2 KO mice to heterozygous and homozygous R47H knock-in mice, which should provide further insight into the specific effects of the R47H allele. For now, we argue that the conclusions that “functional data derived from Trem2 R47H knock-in mice cannot be translated to humans” put forward in this manuscript may be a bit premature because full-length transcripts containing the R47H mutation are still generated in these models, albeit at reduced levels. Notably, all of the strategies to generate TREM2 R47H mice have unique strengths and weaknesses, which makes it difficult to exactly match expression levels of wild-type and R47H-containing TREM2 and/or examine the potential impact on expression of other TREM and TREM-like genes within the locus. The MODEL-AD consortium is currently considering alternative strategies to generate TREM2 R47H models that do not exhibit the effects on mouse TREM2 splicing, and we look forward to obtaining input from the scientific community as we move forward with these efforts.

By Bruce Lamb, representing the IU/JAX MODEL-AD Center.

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