EMC10 reduction in human neurons and adult mouse brain rescues cellular and behavioral deficits linked to 22q11.2 deletion

Thakur, P.; Lackinger, M.; Diamantopoulou, A.; Rao, S.; Chen, Y.; Ferng, A.; Mazur, C.; Kordasiewicz, H.; Shprintzen, R. J.; Markx, S.; Xu, B.; Gogos, J. A.

doi:10.1101/2022.03.01.482495

bioRxiv · 10.1101/2022.03.01.482495

EMC10 reduction in human neurons and adult mouse brain rescues cellular and behavioral deficits linked to 22q11.2 deletion

Thakur, P.·Lackinger, M.·Diamantopoulou, A.·Rao, S.·Chen, Y.·Ferng, A.·Mazur, C.·Kordasiewicz, H.·Shprintzen, R. J.·Markx, S.·Xu, B.·Gogos, J. A.

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Abstract

Adults and children with the 22q11.2 Deletion Syndrome demonstrate cognitive, social and emotional impairments and high risk for schizophrenia. Work in mouse model of the 22q11.2 deletion provided compelling evidence for abnormal expression and processing of microRNAs. A major transcriptional effect of the microRNA dysregulation is up-regulation of Emc10, a component of the ER membrane complex, which promotes membrane insertion of a subset of polytopic and tail-anchored membrane proteins. We previously uncovered a key contribution of EMC10 in mediating the behavioral phenotypes observed in 22q11.2 deletion mouse models. Here we show that expression and processing of miRNAs is abnormal and EMC10 expression is elevated in neurons derived from 22q11.2 deletion carriers. Reduction of EMC10 levels restores defects in neurite outgrowth and calcium signaling in patient neurons. Furthermore, antisense oligonucleotide administration and normalization of Emc10 in the adult mouse brain not only alleviates cognitive deficits in social and spatial memory but remarkably sustains these improvements for over two months post injection, indicating its therapeutic potential. Broadly, our study integrates findings from both animal models and human neurons to elucidate the translational potential of modulating EMC10 levels and downstream targets as a specific venue to ameliorate disease progression in 22q11.2 Deletion Syndrome.

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Thakur, P., Lackinger, M., Diamantopoulou, A., Rao, S., Chen, Y., Ferng, A., Mazur, C., Kordasiewicz, H., Shprintzen, R. J., Markx, S., Xu, B., Gogos, J. A.. 2022-03-04. EMC10 reduction in human neurons and adult mouse brain rescues cellular and behavioral deficits linked to 22q11.2 deletion. https://doi.org/10.1101/2022.03.01.482495

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