The extracellular milieu, including extracellular vesicles (EVs), plays a pivotal role in brain development. In this study, we sought to elucidate the pathogenesis of progressive myoclonus epilepsy type 1 (EPM1), a disease caused by mutations in the CSTB gene, using cerebral organoids (COs) derived from patient cells. The results demonstrate that EPM1 COs display increased electrophysiological activity and disrupted excitatory/inhibitory (E/I) balance. Singlecell RNA sequencing analysis of ventral EPM1-COs revealed an abnormal specification of progenitor fate, with a shift toward dorsal neuron identities. We demonstrated that this misspecification is driven by a functional alteration of the ventral signaling niche, resulting from impaired EV dynamics and altered protein cargo. Mechanistically, we identified Sonic Hedgehog (SHH) as a direct physical interactor of CSTB and demonstrated that CSTB deficiency leads to reduced SHH content and secretion. Our findings establish CSTB as a safeguard of ventral patterning and identify the CSTB-SHH-EV axis as a potential therapeutic target for mitigating the E/I imbalance associated with EPM1.
Defective EV-mediated transport of SHH alters neural fate specification in EPM1 epilepsy / Forero, A., Pravata, V., Pipicelli, F., Frenna, E., Soloperto, A., Ianni, M., Abate, N., Matteo, F.D., Bekjarova, Z., Canafoglia, L., Ragona, F., Maccarrone, G., Pisfil, M.G., Whal-Schott, C., Cernilogar, F.M., Eder, M., Di Giaimo, R., Cappello, S.. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 12:36(2026). [10.1126/sciadv.adu3955]
Defective EV-mediated transport of SHH alters neural fate specification in EPM1 epilepsy
Pipicelli F.Methodology
;Frenna E.Methodology
;Ianni M.Methodology
;Abate N.Methodology
;Di Giaimo R.
Co-ultimo
Conceptualization
;
2026
Abstract
The extracellular milieu, including extracellular vesicles (EVs), plays a pivotal role in brain development. In this study, we sought to elucidate the pathogenesis of progressive myoclonus epilepsy type 1 (EPM1), a disease caused by mutations in the CSTB gene, using cerebral organoids (COs) derived from patient cells. The results demonstrate that EPM1 COs display increased electrophysiological activity and disrupted excitatory/inhibitory (E/I) balance. Singlecell RNA sequencing analysis of ventral EPM1-COs revealed an abnormal specification of progenitor fate, with a shift toward dorsal neuron identities. We demonstrated that this misspecification is driven by a functional alteration of the ventral signaling niche, resulting from impaired EV dynamics and altered protein cargo. Mechanistically, we identified Sonic Hedgehog (SHH) as a direct physical interactor of CSTB and demonstrated that CSTB deficiency leads to reduced SHH content and secretion. Our findings establish CSTB as a safeguard of ventral patterning and identify the CSTB-SHH-EV axis as a potential therapeutic target for mitigating the E/I imbalance associated with EPM1.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
