Jun 2026· Journal of Neurodevelopmental Disorders· 0 citations
Medicine
TL;DR
Findings strongly suggest that altered mitochondrial morphology in DRP1 mutant neurons leads to pathogenic dysregulation of synaptic development and activity.
Abstract
With the advent of exome sequencing, a growing number of children are being identified with de novo loss-of-function mutations in the dynamin 1-like (DNM1L) gene, which encodes the large GTPase essential for mitochondrial fission, dynamin-related protein 1 (DRP1). Mutations in DRP1 result in severe neurodevelopmental phenotypes, such as developmental delay, optic atrophy, and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in different domains of DRP1 uniquely disrupt cortical development and synaptic maturation. We leveraged the power of human induced pluripotent stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model early stages of cortical development in vitro. High-resolution time-lapse imaging of transport in neuronal projections revealed mutation-specific changes in mitochondrial motility of severely hyperfused mitochondrial structures. Transcriptional profiling of mutant DRP1 cortical neurons during maturation also implicated mutation-dependent alterations in synaptic development and gene expression of calcium-regulatory genes. Disruptions in calcium dynamics were confirmed using live functional recordings of 65-200 days in vitro (DIV) mutant DRP1 cortical neurons. These findings strongly suggest that altered mitochondrial morphology in DRP1 mutant neurons leads to pathogenic dysregulation of synaptic development and activity.
Combined transcriptomics profiling in cyp2u1-/- zebrafish and SPG56 patient iPSC-derived cortical neurons supports impaired neural network development as a key disease mechanism.
D. Galatolo, Devid Damiani, V. Naef et al.· Human Molecular Genetics· 0 citations
Ataxia with oculomotor apraxia type 1 (AOA1), caused by mutations in the DNA repair protein aprataxin (APTX), leads to progressive neurodegeneration. In this study, we established an AOA1 patient-derived induced pluripotent stem cell (iPSC) and a neuronal differentiation model. We demonstrated that AOA1-derived neurons exhibit neurite morphology and maturation defects correlated with the accumulation of DNA single-strand break (SSB) signals. AOA1-derived neurons showed greater DNA-damage and PAR signals together with lower protein-normalized NAD(H) and ATP after genotoxic exposure. These parallel changes are consistent with metabolic stress but do not establish a PARP1-dependent causal pathway. Bulk transcriptomic profiling and alternative splicing (AS) analysis further revealed widespread transcriptomic dysregulation and altered AS events, particularly enriched in neuronal genes essential for neurite development and synaptic function. Collectively, our findings identify neuronal differentiation, DNA-damage, metabolic, and transcriptomic differences in AOA1 patient-derived cultures and motivate composition-controlled and rescue-based studies of APTX function.
Zirui Chen, Yihua Huang, Xinyue Hu et al.· Neurobiology of Disease· 0 citations
Myotonic dystrophy type 1 (DM1) is caused by an expansion of a CTG repeat in the 3′ untranslated region of the DMPK gene, leading to accumulation of toxic CUG-repeat RNAs, sequestration of MBNL proteins and widespread splicing dysregulation. Congenital DM1 (CDM), the most severe form of the disease, is associated with profound muscular and neurodevelopmental defects, yet the mechanisms underlying early human brain involvement remain poorly understood. Here, we generated cortical organoids from patient-derived pluripotent stem cells carrying >1000 CTG repeats, an expansion typically associated with CDM, to model early human neurodevelopment. DM1 molecular and cellular hallmarks were detected at early developmental stages, including nuclear DMPK RNA foci in neural progenitor cells and reduced proliferative capacity. As organoids matured, CDM cultures displayed altered cortical composition, with reduced CTIP2⁺ and SATB2⁺ neuronal populations and increased NFIA⁺/GFAP⁺ glial cells. In parallel, 120-day-old organoids recapitulated splicing abnormalities previously identified in DM1 patient brain tissue. To assess the contribution of MBNL dysfunction, we analyzed cortical organoids derived from MBNL2 and MBNL1/2/3 knockout induced pluripotent stem cells, which reproduced key neurodevelopmental phenotypes observed in CDM organoids, supporting a central role for MBNL loss of function in impaired corticogenesis. Finally, we evaluated the translational relevance of this model using tideglusib and erythromycin, two compounds currently under clinical evaluation in DM1 patients. Both treatments reduced DMPK RNA foci and restored proliferation defects in SOX2⁺ neural progenitors. Together, these findings establish cortical organoids as a robust human model of CDM-associated neurodevelopmental defects, uncover MBNL-dependent mechanisms underlying early corticogenesis impairment and demonstrate the utility of this platform for translational therapeutic discovery in DM1.
Azania Abatan, Jérôme Polentes, M. Bouquier et al.· bioRxiv· 0 citations
Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and the subsequent loss of the RNA-binding protein FMRP. N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. FMRP binds and regulates the stability of m6A-containing transcripts. However, how FMRP deficiency impacts transcriptome-wide m6A modifications in FXS remains unknown. To address this, we generated cortical neurons from induced pluripotent stem cells (iPSCs) derived from healthy individuals and FXS patients. Electrophysiology recordings revealed synaptic and neuronal network defects in FXS iPSC-derived neurons. Transcriptome-wide analysis revealed striking m6A hypermethylation predominantly affecting synapse-associated transcripts. Mechanistically, we demonstrated that FMRP deficiency drives the aberrant translational upregulation of core m6A writers, a causal relationship definitively validated using CGG-corrected isogenic control lines. Targeted genetic knockdown of the m6A writer METTL3 successfully rescued synaptic phenotypes in FXS neurons, whereas its overexpression in control neurons phenocopied these synaptic defects, confirming the causal role of m6A dysregulation in FXS pathology. Notably, pharmacological intervention with the METTL3 inhibitor STM-2457 normalized methylation on synapse-associated transcripts and restored synaptic transmission in FXS neurons. Together, our findings uncover an FMRP-dependent epitranscriptomic mechanism contributing to FXS pathogenesis and suggest a promising avenue for m6A-targeted therapies.
Lu Lu, Avijite Kumer Sarkar, Lan Dao et al.· Molecular Psychiatry· 0 citations
The findings implicate DCLK1 in a previously unrecognized progressive neurodevelopmental disorder and demonstrate the power of integrative cross-species functional genomics in resolving ultra-rare disease variants.
Stephen C. Pak, David Butler, Wei-Xi Yuan et al.· Research Square· 0 citations
It is demonstrated that SYNGAP1 haploinsufficiency disrupts early human brain development and accelerates intrinsic neuronal maturation, with pathogenic mechanisms emerging before synaptogenesis and extending beyond SYNGAP1’s established synaptic role.
Montanna Waters, Lucas Teasdale, Sean Byars et al.· bioRxiv· 0 citations