TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43Q331K knock-in mouse model

• DOI: 10.1038/s42003-025-07752-2
• Publication Date: 2025-02-26T15:16:03Z
• Authors: Cha Yang; Gwang Bin Lee; Ling Hao; Fenghua Hu
• Keywords: Knockout mouse; Gene knockin

The TMEM106B gene, encoding a lysosomal membrane protein, is closely linked with brain aging and neurodegeneration. has been identified as risk factor for several neurodegenerative diseases characterized by aggregation of the RNA-binding protein TDP-43, including frontotemporal lobar degeneration (FTLD) limbic-predominant age-related TDP-43 encephalopathy (LATE). To investigate role in proteinopathy, we ablated TDP-43Q331K knock-in mouse line, which expresses an ALS-linked mutation at endogenous levels. We found that deficiency leads to glial activation, Purkinje cell loss, behavioral deficits mice without inducing typical pathology. Interestingly, ablation results significant body weight gain, increased fat deposition, hepatic triglyceride (TG) accumulation mice. In addition, lipidomic transcriptome analysis shows profound alteration lipid metabolism liver TDP-43Q331KTmem106b−/− Our studies reveal novel function provide new insights into their roles An unexpected obesity phenotype altered TMEM106B-deficient metabolism, providing