Biology subjects

Wolf, N. I.

Publications and source records attributed to Wolf, N. I..

2 recordsLinked to original sources

bioRxiv2025

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.

genetics↗

bioRxiv2019

Heterozygous variants in the mechanosensitive ion channel TMEM63A result in transient hypomyelination during infancy

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a mechanically activated (MA) ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modelled variants results in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after four years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.

genomics↗