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TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy

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Abstract

TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes. We found that TMEM106B deletion accelerated cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology. Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on sequelae of tauopathy. Our study further demonstrates that the coding variant is functionally relevant and contributes to neuroprotection downstream of tau pathology to preserve cognitive function.

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Data availability

RNA-seq data from this study was deposited at Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) under accession ID GSE223376.

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Acknowledgements

We thank Philip De Jager for sharing then-unpublished data on the link between TMEM106B and cognitive resilience that sparked our original interest in this protein. We thank Chelsea Jiaqi Zong, Zoe Lai, Jennifer Saldana, and Melissa Comstock for support with the mouse colonies; Gabriella Perez for help with imaging, Cecilia Ljungberg for help with slide scanning, I-Chih Tan for equipment support and repair, and Denise Lanza, Lan Liao, and Jason Heaney for help with mouse creation and cryorecovery. TMEM106B knockout germplasm was provided by the KnockOut Mouse Project (KOMP) Repository and the Mouse Biology Program at the University of California Davis from ES cells generated by the Wellcome Trust Sanger Institute. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org). The specific human AD RNAseq datasets used here were generated by: 1) the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. 2) Dr. Allan Levey from Emory University based on postmortem brain tissue collected by Dr. Eric Schadt from the Mount Sinai School of Medicine through the Mount Sinai VA Medical Center Brain Bank, and 3) the Mayo RNAseq study led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL.

Funding

This work was supported by National Institutes of Health grants R21AG056028, RF1AG058188, and P01AG066606-01A1 and -S1 (JLJ), R01AG074009 (IAR and JLJ), F31AG067676-01A1 (CAW), and T32NS043124 (support for GAE), Alzheimer’s Association grant ZEN-19–591129 (JLJ), and by Federal Work Study funds to BCM (support for QN and PJK). This work was assisted by several advanced technology core laboratories at BCM, including the RNA In Situ Hybridization Core, Bioengineering Core, and Genetically Engineered Rodent Models Core. BCM core laboratories were funded in part by National Institutes of Health grants S10 OD016167 and P50 HD103555 (RNA ISH), P30 CA125123 (GERM), and P30 EY002520 (Bioeng).

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Authors and Affiliations

  1. Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM295, Houston, TX, 77030, USA

    George A. Edwards III, Caleb A. Wood, Quynh Nguyen, Peter J. Kim, Ruben Gomez-Gutierrez, Kyung-Won Park & Joanna L. Jankowsky

  2. Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA

    Yang He & Yong Xu

  3. Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA

    Joanna L. Jankowsky

  4. Department of Neurosurgery, Baylor College of Medicine, Houston, TX, 77030, USA

    Joanna L. Jankowsky

  5. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Joanna L. Jankowsky

  6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Ismael Al-Ramahi

  7. Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Yong Xu

  8. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, 77030, USA

    Yang He

  9. NeuroScience Associates, 10915 Lake Ridge Drive, Knoxville, TN, 37934, USA

    Cody Zurhellen

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  1. George A. Edwards III
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Contributions

JLJ and IAR conceptualized the study; GAE, YH, QN, KWP, RGG, CZ, and PJK performed experimental investigation; GAE, CAW, QN, and IAR contributed to formal analysis; JLJ, CAW, and IAR wrote the paper; JLJ, CAW, YX, and IAR obtained funding for the work.

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Correspondence to Joanna L. Jankowsky.

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CZ is a paid employee of NeuroScience Associates. The remaining authors declare no competing interests.

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Edwards, G.A., Wood, C.A., He, Y. et al. TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy. Acta Neuropathol 147, 61 (2024). https://doi.org/10.1007/s00401-024-02701-5

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