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

Lu Wang, Zhen Li, David Sievert, Desirée E. C. Smith, Marisa I. Mendes, Dillon Y. Chen, Valentina Stanley, Shereen Ghosh, Yulu Wang, Majdi Kara, Ayca Dilruba Aslanger, Rasim O. Rosti, Henry Houlden, Gajja S. Salomons and Joseph G. Gleeson ()
Additional contact information
Lu Wang: University of California San Diego
Zhen Li: University of California San Diego
David Sievert: University of California San Diego
Desirée E. C. Smith: Amsterdam Gastroenterology & Metabolism
Marisa I. Mendes: Amsterdam Gastroenterology & Metabolism
Dillon Y. Chen: Rady Children’s Hospital
Valentina Stanley: University of California San Diego
Shereen Ghosh: University of California San Diego
Yulu Wang: Chinese Academy of Agricultural Sciences
Majdi Kara: University of Tripoli, Tripoli Children’s Hospital
Ayca Dilruba Aslanger: Koç University Hospital
Rasim O. Rosti: University of California San Diego
Henry Houlden: UCL Institute of Neurology
Gajja S. Salomons: Amsterdam Gastroenterology & Metabolism
Joseph G. Gleeson: University of California San Diego

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17454-4

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