Determining the Pathogenesis of Dystonia in Reprogrammed Human Neurons
Abstract
The limited access to patient neurons greatly impedes the progress of research in dystonia. The major purpose of this project is to develop a novel cellular model system for dystonia research. We have successfully generated human patient-specific neurons through either direct conversion of patients' skin fibroblasts or differentiation of induced pluripotent stem cells (iPSCs). We found that dystonia neurons show developmental delay, thickened nuclear lamina,disrupted nuclear morphology, and impaired nucleocytoplasmic transport. Furthermore, we have uncovered that nuclear lamina protein LMNB'I is upregulated in DYT1 neurons and exhibits abnormal subcellular distribution in a cholinergic motor neuron (MN)-specific manner. Interestingly, downregulation of LMNB1 can largely ameliorate all the cellulardefects in DYT'I MNs. These results reveal high value of disease modeling with human patient-specific neurons and indicate that dysregulation of nuclear LMNB1 may constitute a major molecular mechanism underlying DYT1 pathology.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2023
- Accession Number
- AD1217483
Entities
People
- Wu Xu
Organizations
- University of Louisiana at Lafayette