Adult-Onset Dystonia with Late-Onset Epilepsy in TUBB4A-Related Hypomyelinating Leukodystrophy-A New Intermediate Phenotype.
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ABSTRACT:
SUBMITTER: Sarkar P
PROVIDER: S-EPMC9350765 | biostudies-literature | 2022 May-Jun
REPOSITORIES: biostudies-literature
Publications
Adult-Onset Dystonia with Late-Onset Epilepsy in <i>TUBB4A</i>-Related Hypomyelinating Leukodystrophy-A New Intermediate Phenotype.
Sarkar Peyalee P Mukherjee Adreesh A Sarkar Sumanta S Agrawal Raju R Dubey Souvik S Pandit Alak A
Annals of Indian Academy of Neurology 20220420 3
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Project description:IntroductionIn the central nervous system (CNS), proper interaction between neuronal and glial cells is crucial for the development of mature nervous tissue. Hypomyelinating leukodystrophies (HLDs) are a group of genetic CNS disorders characterized by hypomyelination and/or demyelination. In these conditions, genetic mutations disrupt the biological functions of oligodendroglial cells, which are responsible for wrapping neuronal axons with myelin sheaths. Among these, an amino acid mutation of the ubiquitin-fold modifier conjugating enzyme 1 (UFC1) is associated with HLD14-related disease, characterized by hypomyelination and delayed myelination in the brain. UFC1 is a critical component of the UFMylation system, functioning similarly to E2-conjugating enzymes in the ubiquitin-dependent protein degradation system.MethodologyWe describe how a missense mutation in UFC1 (p.Arg23Gln) leads to the aggregation of UFC1 primarily in lysosomes in FBD-102b cells, which are undergoing oligodendroglial cell differentiation.ResultsCells with mutated UFC1 exhibit reduced Akt kinase phosphorylation and reduced expression of differentiation and myelination marker proteins. Consistently, these cells exhibit impaired morphological differentiation with a reduced ability to extend widespread membranes. Interestingly, hesperetin, a citrus flavonoid with known neuroprotective properties, was found to restore differentiation abilities in cells with the UFC1 mutation.ConclusionsThese findings indicate that the HLD14-related mutation in UFC1 causes its lysosomal aggregation, impairing its morphological differentiation. Furthermore, the study highlights potential therapeutic insights into the pathological molecular and cellular mechanisms underlying HLD14 and suggests hesperetin as a promising candidate for treatment.
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