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<p>The <i>TMEM106B</i> gene, encoding a lysosomal membrane protein, is closely linked with brain aging and neurodegeneration. <i>TMEM106B</i> 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-43<sup>Q331K</sup> 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-43<sup>Q331K</sup> 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-43<sup>Q331K</sup> mice. In addition, lipidomic and transcriptome analysis shows a profound alteration in lipid metabolism in the liver of TDP-43<sup>Q331K</sup><i>Tmem106b</i><sup><i>−/−</i></sup> mice. Our studies reveal a novel function of TMEM106B and TDP-43 in lipid metabolism and provide new insights into their roles in neurodegeneration.</p>

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

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  • 出版模式：

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  • 发表日期：

    2025年2月26日

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  • Cha Yang,
  • Gwang Bin Lee,
  • Ling Hao,
  • Fenghua Hu

摘要

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.