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Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice

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Abstract

TMEM106B, a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently, TMEM106B polymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting in severe neuronal loss in the PS19 Tau transgenic mice. Moreover, Tmem106b−/− PS19 mice develop significantly increased abnormalities in the neuronal cytoskeleton, autophagy-lysosome activities, as well as glial activation, compared with PS19 and Tmem106b−/− mice. Together, our findings demonstrate that loss of TMEM106B drastically exacerbates Tau pathology and its associated disease phenotypes, and provide new insights into the roles of TMEM106B in neurodegenerative diseases.

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Data availability

The data supporting the findings of this study are included in the supplemental material. Additional data are available from the corresponding author on request. No data are deposited in databases.

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Acknowledgements

We would like to thank Xiaochun Wu for technical assistance, Dr. Tony Bretscher’s lab for assistance with the confocal microscope and Dr. Chris Schaffer and Dr. Nozomi Nishimura’s group for help with behavioral tests. We also thank the late Professor Chad Dickey (University of South Florida) for providing DyLight 488-Tau P301L oligomer. This work is supported by NINDS/NIA (R01NS088448 & R01NS095954) to F.H.

Funding

National Institute of Neurological Disorders and Stroke, R01NS088448, Fenghua Hu, R01NS095954, Fenghua Hu.

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Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, 345 Weill Hall, Ithaca, NY, 14853, USA

    Tuancheng Feng, Huan Du, Cha Yang, Ya Wang & Fenghua Hu

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  1. Tuancheng Feng
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Contributions

T.F. characterized all the phenotypes, analyzed the data, and drafted the manuscript. H.D. and T.F. bred the mice. C.Y. and Y.W. performed behavioral tests. F.H. supervised the project and edited the manuscript. All authors have read and approved the manuscript.

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Correspondence to Fenghua Hu.

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Conflict of interest

F.H. serves as a member of SAB of Muna Therapeutics and a consultant for Alector, Guidepoint, and GLG. Other authors have no competing interests.

Ethical approval and consent to participate

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The work under animal protocol 2017-0056 is approved by the Institutional Animal Care and Use Committee at Cornell University.

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Feng, T., Du, H., Yang, C. et al. Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice. Acta Neuropathol 147, 62 (2024). https://doi.org/10.1007/s00401-024-02702-4

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