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TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination
Julia Halford1, Amanda J Senatore1, Sage Berryman1
1Vollum Institute, Oregon Health & Science University, Portland, OR 97239.
Abstract:
Infantile hypomyelinating leukodystrophy 19 (HLD19) is a rare genetic disorder where patients exhibit reduced myelin in central nervous system (CNS) white matter tracts and present with varied neurological symptoms. The causative gene TMEM63A encodes a mechanosensitive ion channel whose role in myelination is largely unexplored. Our study shows that TMEM63A is a major regulator of oligodendrocyte (OL)-dependent myelination in the CNS. In mouse and zebrafish, Tmem63a inactivation led to early deficits in myelination, recapitulating the HLD19 phenotype. OL-specific conditional mouse knockouts of Tmem63a exhibited transient reductions in myelin, indicating that TMEM63A regulates myelination cell-autonomously. We show that TMEM63A is present at the plasma membrane and on lysosomes and modulates myelin production in the presence of mechanical cues. Intriguingly, HLD19-associated TMEM63A variants from patients blocked trafficking to cell membrane. Together, our results reveal an ancient role for TMEM63A in fundamental aspects of myelination in vivo and highlight two exciting models for the development of treatments for devastating hypomyelinating leukodystrophies.
Insights
TMEM63A is crucial for oligodendrocyte myelination in the central nervous system (CNS). Mutations in TMEM63A cause infantile hypomyelinating leukodystrophy 19 (HLD19), offering new therapeutic targets.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Infantile hypomyelinating leukodystrophy 19 (HLD19) is a rare genetic disorder characterized by reduced central nervous system (CNS) myelin.
- The gene TMEM63A, encoding a mechanosensitive ion channel, is implicated in HLD19, but its function in myelination is unknown.
Purpose of the Study:
- To investigate the role of TMEM63A in oligodendrocyte (OL)-dependent myelination.
- To explore the mechanism by which TMEM63A regulates myelination and its relevance to HLD19.
Main Methods:
- Utilized mouse and zebrafish models with Tmem63a inactivation.
- Generated OL-specific conditional mouse knockouts of Tmem63a.
- Investigated TMEM63A localization and function in response to mechanical cues.
- Analyzed patient-derived TMEM63A variants.
Main Results:
- Tmem63a inactivation in mice and zebrafish led to myelination deficits, mimicking HLD19.
- OL-specific knockouts showed transient myelin reductions, indicating cell-autonomous regulation by TMEM63A.
- TMEM63A localizes to the plasma membrane and lysosomes, modulating myelin production under mechanical stimulation.
- HLD19 variants impaired TMEM63A trafficking to the cell membrane.
Conclusions:
- TMEM63A is a key regulator of CNS myelination, acting cell-autonomously in oligodendrocytes.
- Dysfunctional TMEM63A, due to genetic variants, causes HLD19 by disrupting myelination.
- This study provides insights into hypomyelinating leukodystrophies and potential therapeutic strategies.
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