Transcriptomic disruption and functional hypoactivity in DYT-SGCE MGE-patterned inhibitory neurons
Li, Z.; Abram, L.; Santos, M. C.; Petter, O.; Peall, K.
Show abstract
Myoclonus Dystonia is a dystonic movement disorder caused by SGCE mutations, the underlying pathophysiology for which remains unclear. Here, we evaluated the impact of SGCE mutations on medial ganglionic eminence (MGE)-derived GABAergic neurons using patient-derived induced pluripotent and gene edited embryonic stem cell lines, each compared to their isogenic wild-type control. No significant differences were observed in markers of neuronal development however, single-cell RNA sequencing demonstrated transcriptomic dysregulation in genes related to axonal organization, synaptic signalling, and action potential generation in the SGCE -mutation harbouring neurons. Functional assays demonstrated reduced neurite outgrowth, lower calcium responses to GABA, and decreased neuronal excitability and network activity in the SGCE -mutant neurons. These findings contrast with the hyperexcitable phenotype previously observed in SGCE -mutant cortical glutamatergic neurons. Collectively, this supports loss of neuronal inhibitory activity, and disruption to the neuronal excitatory/inhibitory balance in motor circuits, in contributing to the overall hyperkinetic clinical phenotype in Myoclonus Dystonia.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Neuronal Modeling of Alternating Hemiplegia of Childhood Reveals Transcriptional Compensation and Replicates a Trigger-Induced Phenotype 95%
- Altered action potential waveform and shorter axonal initial segment in hiPSC-derived motor neurons with mutations in VRK1 95%
- Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation 95%
Similar papers in this journal
- Variability vs Phenotype: multimodal analysis of Dravet Syndrome Brain Organoids powered by Deep Learning 94%
- Sustained Generation of Neurons Destined for Neocortex with Oxidative Metabolic Upregulation upon Filamin Abrogation 93%
- Transcriptome profiling of the Olig2-expressing astrocyte subtype reveals their unique molecular signature 93%
Similar papers in this journal
- Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway 95%
- Mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity 94%
- Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins 94%
Similar papers in this journal
- Defective DcpS Decapping Manifests in Creatine Deficiency Syndrome and Neurological impairment 95%
- Human Cerebral Spheroids Undergo Activity Dependent Changes In Cellular Composition And MicroRNA Expression 93%
- MHCII reduction is insufficient to protect mice from alpha-synuclein-induced degeneration and the Parkinson's HLA locus exhibits epigenetic regulation 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.