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Werner G, Damme M, Schludi M, Gnörich J, Wind K, Fellerer K, Wefers B, Wurst W, Edbauer D, Brendel M, Haass C, Capell A. Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice. EMBO Rep. 2020 Oct 5;21(10):e50241. Epub 2020 Sep 14 PubMed.
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Yale University School of Medicine
We are delighted that the three TMEM106B/PGRN double knockout studies from Zhou et al., Feng et al., and Werner et al. have further clarified the genetic interactions between TMEM106B and GRN. Full deletion of both genes clearly causes a synthetic lethal phenotype with motor dysfunction. The new results are distinctly different from our previous publication on this topic in 2017, which documented normalization of Grn-/- proteomic changes and reduced retinal degeneration in young TMEM106B/PGRN double gene-targeted mice.
Based on the report from the Rademakers laboratory of a TMEM106B gene trap line, we have examined the TMEM106B gene trap line that we used. Indeed, we confirm the Zhou et al. finding that TMEM106B gene trap mouse brain has about 5 percent residual full-length TMEM106B protein. This is presumably due to exon-skipping over the gene trap insertion during mRNA processing. In our case, this was observed by IP-western blot analysis, and confirmed by mass spectrometric peptide identification. We did not include a Cre recombinase cross to fully remove any TMEM106B coding exon (as was done in the Werner et al. paper), so the possibility of a spliced, full-length TMEM106B transcript always existed.
Thus, the partial rescue phenotype we observed for TMEM106B reduction in Grn-/- mice at young-adult ages appears to depend on the allele being a hypomorph as opposed to a complete null. With the various complete null TMEM106B mice generated in the new studies, there is clearly a synthetic lethal phenotype by 4-5 months.
Moreover, while the hypomorphic TMEM106B allele rescues some Grn-/- phenotypes at the 4- to 7-month time window, we have observed a severe, double-knockout motor phenotype beginning at 11 months that causes death. The latter is consistent with the description of gene trap hypomorphic mice in Zhou et al. (as opposed to early death in the CRISPR null line) and closely resembles the phenotype of 4- to 5-month-old, double-knockout mice with the complete null alleles.
It appears that certain Grn-/- phenotypes have a non-linear and biphasic dependence on reducing TMEM106B levels, and it is now clear that a full double knockout yields lethality.
It is critical to note that none of these TMEM106B alleles on the Grn-/- background accurately models human FTLD-GRN with TMEM10B variants. In such clinical cases, there is only 50 percent reduction of PGRN expression, and the risk variants for the TMEM106B locus reportedly cause moderate changes in expression. Thus, continued investigation of GRN interaction with TMEM106B in neurodegeneration is required.
—Hideyuki Takahashi is a co-author of this comment.
View all comments by Stephen StrittmatterUniversity of Kiel
As a minor addition to the comment: The cre-mediated Tmem106b full knockout used for generating the GRN/TMEM106B double knockout of the DZNE study was published before and was generated in the lab of Christian Haass. This strain was analyzed in parallel to the CRISPR-mediated Tmem106b knockout in my group in collaboration with Christian Haass and Anja Capell and, importantly, both showed a phenocopy and drastically enlarged vacuoles positive for lysosomal marker proteins.
References:
Lüningschrör P, Werner G, Stroobants S, Kakuta S, Dombert B, Sinske D, Wanner R, Lüllmann-Rauch R, Wefers B, Wurst W, D'Hooge R, Uchiyama Y, Sendtner M, Haass C, Saftig P, Knöll B, Capell A, Damme M. The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons. Cell Rep. 2020 Mar 10;30(10):3506-3519.e6. PubMed.
View all comments by Markus DammeMake a Comment
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