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Cover ArticleResearch Articles, Cellular/Molecular

An Autism-Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons

Thomas P. Cast, Daniel J. Boesch, Kim Smyth, Alisa E. Shaw, Michael Ghebrial and Soham Chanda
Journal of Neuroscience 20 January 2021, 41 (3) 392-407; DOI: https://doi.org/10.1523/JNEUROSCI.0404-20.2020
Thomas P. Cast
1Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado 80523
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Daniel J. Boesch
1Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado 80523
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Kim Smyth
2Pediatric Neurology, University of Calgary, Calgary, Alberta T3B 6A8, Canada
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Alisa E. Shaw
1Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado 80523
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Michael Ghebrial
3Biological Science, California State University Fullerton, Fullerton, California 92831
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Soham Chanda
1Biochemistry & Molecular Biology, Colorado State University, Fort Collins, Colorado 80523
4Molecular, Cellular & Integrated Neurosciences, Colorado State University, Fort Collins, Colorado 80523
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Abstract

Neuroligins (NLGNs) are a class of postsynaptic cell adhesion molecules that interact with presynaptic neurexins (NRXNs) and regulate synapse function. NLGN4 is a member of the NLGN family and consists of a unique amino acid sequence in humans that is not evolutionarily well conserved in rodents. The human-specific NLGN4 gene has been reported to be mutated in many patients with autism and other neurodevelopmental disorders. However, it remained unclear how these mutations might alter the molecular properties of NLGN4 and affect synaptic transmission in human neurons. Here, we describe a severely autistic male patient carrying a single amino acid substitution (R101Q) in the NLGN4 gene. When expressed in HEK293 cells, the R101Q mutation in NLGN4 did not affect its binding affinity for NRXNs or its capacity to form homodimers. This mutation, however, impaired the maturation of NLGN4 protein by inhibiting N-linked glycosylation at an adjacent residue (N102), which is conserved in all NLGNs. As a result, the R101Q substitution significantly decreased the surface trafficking of NLGN4 and increased its retention in the endoplasmic reticulum and Golgi apparatus. In human neurons derived from male stem cell lines, the R101Q mutation also similarly reduced the synaptic localization of NLGN4, resulting in a loss-of-function phenotype. This mutation-induced trafficking defect substantially diminished the ability of NLGN4 to form excitatory synapses and modulate their functional properties. Viewed together, our findings suggest that the R101Q mutation is pathogenic for NLGN4 and can lead to synaptic dysfunction in autism.

  • AMPA receptor
  • autism
  • glycosylation
  • neuroligin-4
  • synaptic transmission
  • trafficking

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The Journal of Neuroscience: 41 (3)
Journal of Neuroscience
Vol. 41, Issue 3
20 Jan 2021
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An Autism-Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons
Thomas P. Cast, Daniel J. Boesch, Kim Smyth, Alisa E. Shaw, Michael Ghebrial, Soham Chanda
Journal of Neuroscience 20 January 2021, 41 (3) 392-407; DOI: 10.1523/JNEUROSCI.0404-20.2020

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An Autism-Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons
Thomas P. Cast, Daniel J. Boesch, Kim Smyth, Alisa E. Shaw, Michael Ghebrial, Soham Chanda
Journal of Neuroscience 20 January 2021, 41 (3) 392-407; DOI: 10.1523/JNEUROSCI.0404-20.2020
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Keywords

  • AMPA receptor
  • autism
  • glycosylation
  • neuroligin-4
  • synaptic transmission
  • trafficking

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