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.

Recommends

Please login to recommend the paper.

Comments

  1. I think this study is important, as it may shed light on the function of TMEM106B, which has emerged as a key genetic risk locus not only for development of FTLD-TDP, but also for rate of progression in clinical FTD and in Parkinson’s disease (Tropea et al., 2019). Specifically, two lines of mice lacking TMEM106B show vacuolization within neurons, and the data suggest that these vacuoles are a type of non-functional, or poorly functional, lysosome.

    These results differ from prior reports of TMEM106B knockout mice, where minimal phenotypes were seen. However, variable phenotypes in what should be equivalent mouse models sometimes happen—the various C9ORF72 expansion mice are a key example. The fact that the authors got this vacuolization phenotype in two lines of knockouts, generated via different strategies, is reassuring. In addition, our work, and the work of other groups, using cells leads us to believe that TMEM106B may regulate aspects of lysosomal function and/or lysosome-autophagosome fusion (Chen-Plotkin et al., 2012; Busch et al., 2016). Their in vivo findings do agree with these expectations.

    References:

    Tropea TF, Mak J, Guo MH, Xie SX, Suh E, Rick J, Siderowf A, Weintraub D, Grossman M, Irwin D, Wolk DA, Trojanowski JQ, Van Deerlin V, Chen-Plotkin AS. TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia. Ann Neurol. 2019 Jun;85(6):801-811. PubMed.

    Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L, Busch JI, Akle S, Grossman M, Van Deerlin V, Trojanowski JQ, Lee VM. TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci. 2012 Aug 15;32(33):11213-27. PubMed.

    Busch JI, Unger TL, Jain N, Tyler Skrinak R, Charan RA, Chen-Plotkin AS. Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Hum Mol Genet. 2016 Apr 28; PubMed.

    View all comments by Alice Chen-Plotkin

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Without TMEM106B, Lysosomal Traffic Jams Wreak Havoc in Neurons