Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Abstract

Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.

Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects

“…Among these, we identify tRNA regulation as one of the most significantly restored pathways in the absence of p19 Arf . Importantly, p19 Arf can directly block tRNA synthesis (27), while disruption of tRNA function is strongly associated with microcephaly and neurodevelopmental disorders (26,(28)(29)(30)(31)(32). Together, our findings support that VPA induction of p19 Arf -mediated senescence causes a broad repression of key developmental pathways, including tRNA function, thereby disrupting early neurodevelopmental steps.…”

A Human 3D neural assembloid model for SARS-CoV-2 infection

“…Cortical brain organoids were generated as previously described 36,37 . For PCCO generation, at CO 60 div, 2x10 5 GFP+ PLCs were integrated into each CO in a low attachment 96-well plate.…”

A Human 3D neural assembloid model for SARS-CoV-2 infection

“…H1 and hiPSCs were maintained in mTeSR and passaged according to manufacturer’s recommendations. Cortical brain organoids were generated as previously described 36,37 . For PCCO generation, at CO 60 div, 2×10 5 GFP+ PLCs were integrated into each CO in a low attachment 96-well plate.…”