Cortical organoids reveal human-specific role of METTL5 in neurodevelopment via regulation of CHCHD2.

Cortical organoids from congenital DM1 PSCs reveal MBNL-dependent corticogenesis defects and enable preclinical testing of therapeutic compounds

Cortical organoids are established 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.

Molecules and Cells

Single-cell transcriptomics identifies neural fate disruption and glial reprogramming caused by RARS2 deficiency.

RARS2 deficiency disrupts mitochondrial integrity and reprograms neural lineage development through coordinated suppression of neurogenic transcriptional networks and activation of glial/ECM programmes.

METTL1-mediated N7-methylguanosine epitranscriptomic alterations modulate mRNA stability of neurodegenerative disease-associated genes following cobalt exposure.

A pivotal role for m7G modification in environmental neurotoxicant-induced neurodegeneration is established and cobalt-related RNA regulatory paradigm is revealed that expands the understanding of heavy metal-driven epitranscriptomic dysregulation, and hence offering novel therapeutic targets.

DEPDC5: Modeling of the Two-Hit Wonder in Cortical Organoids

Mosaic Human Cortical Organoids Model 1 mTOR-Related Focal Cortical Dysplasia 2 Through DEPDC5 Deletion Maletic M, Bizzotto S, Ribierre T, Guerdoud K, Raoux C, Doladilhe M, Dalle C, Picard F, Baulac S. Brain 2026:awag086. doi: 10.1093/brain/awag086. Online ahead of print. PMID: 41789478 Focal cortical dysplasia type II (FCDII), a major cause of pediatric drug-resistant focal epilepsy, results from brain somatic variants in the mechanistic target of rapamycin (mTOR) pathway genes, including germline and somatic second-hit loss-of-function variants in the mTOR repressor DEPDC5. Here, we present a proof-of-concept model of DEPDC5 two-hit inactivation mosaicism using patient-derived human cortical organoids (hCOs). Mosaic hCOs displayed increased mTOR activity that was rescued by the mTOR inhibitor rapamycin. Mosaic hCOs also exhibited dysmorphic-like neurons and enhanced neuronal excitability, recapitulating key FCDII pathology hallmarks. Single-cell transcriptomics across 3 developmental stages revealed aberrant differentiation trajectories leading to premature upper-layer neuron generation, upregulated Notch and Wnt signaling pathways in neural progenitors, and altered expression of synaptic- and epilepsy-associated genes in excitatory neurons. In addition, we identified cell-autonomous alterations in metabolism and translation in mosaic DEPDC5 two-hit hCOs. This study provides novel insights into how DEPDC5 deficiency perturbs human corticogenesis, highlighting that mosaic bi-allelic inactivation of the gene is necessary for FCDII pathogenesis.

Central Thyroid Hormone Deprivation Disrupts Cortical Cilia and Oligodendrocyte Lineage in an Allan–Herndon–Dudley Syndrome Mouse Model

These findings provide the first single-cell–level cortical map of AHDS brain pathology, revealing cilia defects, excitation–inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS.