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

Authors: EDWARDS, GEORGE - Baylor College Of Medicine; WOOD, CALEB - Baylor College Of Medicine; HE, YANG - Baylor College Of Medicine; NGUYEN, QUYNH - Baylor College Of Medicine; KIM, PETER - Baylor College Of Medicine; GOMEZ-GUTIERREZ, RUBEN - Baylor College Of Medicine; PARK, KYUNG-WON - Baylor College Of Medicine; XU, YONG - Children'S Nutrition Research Center (CNRC); ZURHELLEN, CODY - Neuroscience Associates; AL-RAMAHI, ISMAEL - Baylor College Of Medicine; JANKOWSKY, JOANNA - Baylor College Of Medicine

Submitted to: Acta Neuropathologica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/31/2024
Publication Date: 5/25/2024
Citation: Edwards, G.A., Wood, C.A., He, Y., Nguyen, Q., Kim, P.J., Gomez-Gutierrez, R., Park, K., Xu, Y., Zurhellen, C., Al-Ramahi, I., Jankowsky, J.L. 2024. TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy. Acta Neuropathologica. 147. Article 61. https://doi.org/10.1007/s00401-024-02701-5.
DOI: https://doi.org/10.1007/s00401-024-02701-5

Interpretive Summary: TMEM106B affects the risk of various neurological diseases through a specific coding variant and several non-coding SNPs. Researchers wanted to know if the T185S coding variant provides protection and whether TMEM106B is helpful or harmful in diseases. They studied mice with a deleted TMEM106B gene and mice with the T186S mutation (similar to human T185S), crossed with a model of tauopathy (a disease with tau protein issues). They found that removing TMEM106B made cognitive decline, limb paralysis, tau protein problems, and brain cell damage happen faster. It also made the mice's disease more similar to Alzheimer's disease. On the other hand, the T186S variant protected the mice from cognitive decline, synapse issues, brain cell damage, and paralysis without affecting tau protein problems. This study shows that TMEM106B helps protect against tau protein issues, and losing it makes tau-related diseases worse. The T186S variant is important because it helps protect brain function despite tau problems.

Technical 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.