TMEM106B Coding Variant Is Protective and Deletion Detrimental in a Mouse Model of Tauopathy

Authors

George A Edwards
Caleb A Wood
Yang He
Quynh Nguyen
Peter J Kim
Ruben Gomez-Gutierrez
Kyung-Won Park
Yong Xu
Cody Zurhellen
Ismael Al-Ramahi
Joanna L Jankowsky

Language

English

Publication Date

3-25-2024

Journal

Acta Neuropathologica

DOI

10.1007/s00401-024-02701-5

PMID

38526616

PMCID

PMC12313335

PubMedCentral® Posted Date

7-31-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Animals, Humans, Mice, Disease Models, Animal, Membrane Proteins, Mice, Knockout, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Paralysis, Polymorphism, Single Nucleotide, tau Proteins, Tauopathies, Tau, Tauopathy, Alzheimer’s disease, Frontotemporal dementia, TMEM106B, Cognitive resilience, Neurodegeneration, Mouse model

Published Open-Access

yes

Recommended Citation

Edwards, George A; Wood, Caleb A; He, Yang; et al., "TMEM106B Coding Variant Is Protective and Deletion Detrimental in a Mouse Model of Tauopathy" (2024). Duncan NRI Faculty and Staff Publications. 121.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/121