TFEB-depletion rescues TMEM106B-related myelin defects in zebrafish

Lysosomal transmembrane protein TMEM106B is genetically and neuropathologically implicated in a range of neurodegenerative diseases. Unexpectedly, the recurrent de novo TMEM106B variant p.(Asp252Asn) causes a hypomyelinating disorder. TMEM106B controls lysosomal positioning in neurons, but its role in white matter health is not fully understood. To study the role of TMEM106B in myelination in vivo, we mutated zebrafish tmem106ba and tmem106bb homologs. In vivo brain imaging in larvae deficient for both homologs (tmem106bdm) showed more, smaller lysosomes, accompanied by reduced myelin content and shorter myelin sheaths. Oligodendrocytes in tmem106bdm exhibited more lysosomes in the perinuclear region. We next genome-edited the pathogenic p.(Asp252Asn) variant into the zebrafish genome and showed that it acts dominant-negatively on myelination and on lysosomal clustering around the nucleus in oligodendrocytes. As lysosomal peri-nuclear positioning modulates mTOR-signaling, and downstream transcription factor EB (TFEB) inhibits myelination, we next investigated whether there is a genetic interaction between TMEM106B and TFEB. Indeed, deficient myelination in tmem106bdm larvae, but not altered lysosomal clustering, was restored by loss of Tfeb in triple mutant larvae. Our work elucidates that TMEM106B modulates myelination by a TFEB-dependent pathway. This implicates the TFEB pathway in myelin development and white matter health and suggests that modulating TFEB could be a therapeutic target in white matter disorders.