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A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination
Tuancheng Feng1, Rory R Sheng1, Santiago Solé-Domènech2
1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University Ithaca, NY 14853, USA.
Abstract:
TMEM106B encodes a lysosomal membrane protein and was initially identified as a risk factor for frontotemporal lobar degeneration. Recently, a dominant D252N mutation in TMEM106B was shown to cause hypomyelinating leukodystrophy. However, how TMEM106B regulates myelination is still unclear. Here we show that TMEM106B is expressed and localized to the lysosome compartment in oligodendrocytes. TMEM106B deficiency in mice results in myelination defects with a significant reduction of protein levels of proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), the membrane proteins found in the myelin sheath. The levels of many lysosome proteins are significantly decreased in the TMEM106B-deficient Oli-neu oligodendroglial precursor cell line. TMEM106B physically interacts with the lysosomal protease cathepsin D and is required to maintain proper cathepsin D levels in oligodendrocytes. Furthermore, we found that TMEM106B deficiency results in lysosome clustering in the perinuclear region and a decrease in lysosome exocytosis and cell surface PLP levels. Moreover, we found that the D252N mutation abolished lysosome enlargement and lysosome acidification induced by wild-type TMEM106B overexpression. Instead, it stimulates lysosome clustering near the nucleus as seen in TMEM106B-deficient cells. Our results support that TMEM106B regulates myelination through modulation of lysosome function in oligodendrocytes.
Insights
TMEM106B protein deficiency in oligodendrocytes impairs myelination by disrupting lysosome function. This leads to reduced myelin proteins and abnormal lysosome clustering, impacting brain development.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- TMEM106B, a lysosomal protein, is linked to frontotemporal lobar degeneration and hypomyelinating leukodystrophy.
- The precise role of TMEM106B in regulating myelination remains largely unknown.
Purpose of the Study:
- To elucidate the function of TMEM106B in oligodendrocyte myelination.
- To investigate the molecular mechanisms by which TMEM106B influences lysosome function and myelin integrity.
Main Methods:
- Analysis of TMEM106B expression and localization in oligodendrocytes.
- Assessment of myelination defects in TMEM106B-deficient mice.
- Investigation of lysosome protein levels and function in TMEM106B-deficient cells.
- Co-immunoprecipitation to study TMEM106B interaction with cathepsin D.
- Evaluation of lysosome morphology and exocytosis.
- Analysis of a disease-associated TMEM106B mutation (D252N).
Main Results:
- TMEM106B is localized to lysosomes in oligodendrocytes and its deficiency causes significant myelination defects.
- Loss of TMEM106B reduces levels of key myelin proteins (PLP, MOG) and lysosomal proteins.
- TMEM106B interacts with cathepsin D, maintaining its levels and proper lysosome function, including exocytosis.
- The D252N mutation impairs TMEM106B's ability to regulate lysosome size and acidity, causing perinuclear lysosome clustering.
Conclusions:
- TMEM106B is crucial for maintaining oligodendrocyte lysosome function and regulating myelination.
- Dysregulation of TMEM106B impacts lysosome homeostasis, leading to myelination deficits relevant to leukodystrophies.
