Human iPSC-Derived Spinal Neurons Carrying the ALS FUS (P525L) Mutation Exhibit Lower Response to Inhibitory Neurotransmitters.

Neural stem cell-derived small extracellular vesicles ameliorate disease progression in the SOD1 G93A murine model of amyotrophic lateral sclerosis.

FUS-driven zebrafish model of ALS identifies tribenzylamine as a candidate modulator of ALS-associated pathology.

Findings support the mtFUS zebrafish model as a useful platform for ALS drug discovery and identify tribenzylamine as a candidate modulator of ALS-associated phenotypes, with effects linked to transcriptomic remodeling and neuronally active sex steroid signaling.

Epilepsy-associated SCN2A-L1342P mutation drives network hyperexcitability and widespread transcriptomic changes in human cortical organoids.

OBJECTIVE SCN2A pathogenic mutations, such as the recurrent heterozygous Nav1.2-L1342P, are monogenic causes of epilepsy. In this human-induced pluripotent stem cell-derived model system, we aim to investigate the molecular and cellular mechanisms underlying SCN2A-L1342P-associated pathology. METHODS Using a human male induced pluripotent stem cell (iPSC) reference line (KOLF) carrying the Nav1.2-L1342P mutation, we generated three-dimensional (3D) cortical organoids for functional studies. Patch-clamp, multi-electrode array (MEA) recordings, immunocytochemistry, and RNA sequencing were used to characterize the disease phenotypes. RESULTS Nav1.2-L1342P organoid neurons displayed increased intrinsic excitability and amplified excitatory post-synaptic currents, which are consistent with an increase in excitatory synapse formation revealed by SYN1/PSD95 immunostaining. Moreover, elevated network firing activity, as demonstrated by MEA, indicates a pronounced network hyperexcitability. Transcriptomic profiling of organoids carrying the Nav1.2-L1342P mutation further revealed significant alterations in synaptic, glutamatergic, developmental, and senescence/apoptotic pathways. SIGNIFICANCE Our findings demonstrate that the Nav1.2-L1342P mutation drives a multifaceted disease phenotype, including network hyperexcitability and disruption of pathways related to neuronal and synaptic functions. These results advance our understanding of SCN2A-related developmental and epileptic encephalopathy (DEE), laying a foundation for personalized interventions.

APTX deficiency is associated with altered neuronal differentiation and alternative splicing in patient-derived neurons.

It is demonstrated that AOA1-derived neurons exhibit neurite morphology and maturation defects correlated with the accumulation of DNA single-strand break (SSB) signals, and DNA-damage and PAR signals showed greater DNA-damage and PAR signals together with lower protein-normalized NAD(H) and ATP after genotoxic exposure.

Deletion of TUBB4A mitigates the oligodendrocyte and neuronal deficits in human iPSCs derived from individuals affected by H-ABC

Neurogenesis defects in iPSC-derived midbrain organoids of early-onset Parkinson's disease with 22q11.2 deletion syndrome

These findings suggest that, in early-onset PD patients with 22q11.2 DS or PRKN mutation, enhanced neurogenesis could result in reduced number of dopaminergic neurons during early development, which indicates that the onset of PD may occur as early as the embryonic stage.