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

Nat Commun. 2020 Aug 12;11(1):4038. doi: 10.1038/s41467-020-17454-4.

Lu Wang ¹ ², Zhen Li ¹ ², David Sievert ^# ¹ ², Desirée E C Smith ^# ³, Marisa I Mendes ^# ³, Dillon Y Chen ² ⁴ ⁵, Valentina Stanley ¹ ², Shereen Ghosh ¹ ², Yulu Wang ⁶, Majdi Kara ⁷, Ayca Dilruba Aslanger ⁸, Rasim O Rosti ¹ ², Henry Houlden ⁹, Gajja S Salomons ³, Joseph G Gleeson ¹⁰ ¹¹ ¹² ¹³

Affiliations

1 Department of Neurosciences, Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, 92093, USA.
2 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA, 92123, USA.
3 Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology & Metabolism, Amsterdam, Netherlands.
4 Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA.
5 Division of Child Neurology, Rady Children's Hospital, San Diego, CA, 92123, USA.
6 Laboratory of Biomanufacturing and Food Engineering, Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, PR China.
7 University of Tripoli, Tripoli Children's Hospital, Tripoli, Libya.
8 Department of Medical Genetics, Koç University Hospital, Istanbul, 34010, Turkey.
9 Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
10 Department of Neurosciences, Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, 92093, USA. jogleeson@health.ucsd.edu.
11 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA, 92123, USA. jogleeson@health.ucsd.edu.
12 Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA. jogleeson@health.ucsd.edu.
13 Division of Child Neurology, Rady Children's Hospital, San Diego, CA, 92123, USA. jogleeson@health.ucsd.edu.
# Contributed equally.

PMID: 32788587 DOI: 10.1038/s41467-020-17454-4

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.

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