Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism
Hideyuki Takahashi, Azucena Pérez‐Cañamás, Chris W. Lee, Hongping Ye, Xianlin Han, Stephen M. Strittmatter
Abstract
TMEM106B is an endolysosomal transmembrane protein not only associated with multiple neurological disorders including frontotemporal dementia, Alzheimer’s disease, and hypomyelinating leukodystrophy but also potentially involved in COVID-19. Additionally, recent studies have identified amyloid fibrils of C-terminal TMEM106B in both aged healthy and neurodegenerative brains. However, so far little is known about physiological functions of TMEM106B in the endolysosome and how TMEM106B is involved in a wide range of human conditions at molecular levels. Here, we performed lipidomic analysis of the brain of TMEM106B-deficient mice. We found that TMEM106B deficiency significantly decreases levels of two major classes of myelin lipids, galactosylceramide and its sulfated derivative sulfatide. Subsequent co-immunoprecipitation assay showed that TMEM106B physically interacts with galactosylceramidase. We also found that galactosylceramidase activity was significantly increased in TMEM106B-deficient brains. Thus, our results suggest that TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism and have implications for TMEM106B-associated diseases. Unbiased lipidomic and proteomic analyses reveal that TMEM106B, an endolysosomal protein associated with many neurological disorders including frontotemporal dementia, regulates myelin lipid metabolism by interacting with galactosylceramidase.