Exploring 4H leukodystrophy using patient samples
2023
Vrije Universiteit Amsterdam, Amsterdam, Netherlands
4H leukodystrophy is a rare genetic disorder usually characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. With the discovery that 4H is caused by mutations affecting RNA polymerase III, which is mainly involved in the transcription of small noncoding RNAs, patients with atypical presentations, mainly showing a neuronal phenotype, have also been identified. The pathomechanisms of 4H brain abnormalities are still unknown. The aim of this study was to identify cells and signaling pathways affected by 4H mutations.
RNA-seq analysis of induced pluripotent stem cell-derived cerebellar cells revealed several differentially expressed genes between 4H patients and control samples, including decreased ARX expression. This correlated with changes in interneurons in the primary tissue of 4H patients. In addition, cortical neurons derived from induced pluripotent stem cells from 4H patients had a decreased proportion of GABA-ergic synapses, which correlated with an increased neuronal network activity. Treatment of cultures with GABA antagonists resulted in a significant increase in neuronal network activity in control cells but not in 4H cells, also suggesting a lack of inhibitory activity in 4H. Myelination and maturation of oligodendrocytes in cultures with 4H neurons were normal, and treatment with the Sonic hedgehog agonist SAG did not improve neuronal phenotypes associated with 4H. Quantitative PCR analysis revealed increased expression of the parvalbumin interneuron marker ERBB4, suggesting that development rather than formation of interneurons may be affected in 4H.
Overall, these results suggest that interneurons, possibly parvalbumin interneurons, are involved in the disease mechanisms of 4H leukodystrophy.
Cortical interneuron development is affected in 4H leukodystrophy
Vivi M. Heine
Added on: 04-27-2023
[1] https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad017/7024729?login=false
