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

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