Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders

Greta Pintacuda; Yu-Han H Hsu; Kalliopi Tsafou; Ka Wan Li; Jacqueline M Martín; Jackson Riseman; Julia C Biagini; Joshua K T Ching; Daya Mena; Miguel A Gonzalez-Lozano; Shawn B Egri; Jake Jaffe; August B Smit; Nadine Fornelos; Kevin C Eggan; Kasper Lage

doi:10.1016/j.xgen.2022.100250

Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders

Cell Genom. 2023 Jan 24;3(3):100250. doi: 10.1016/j.xgen.2022.100250. eCollection 2023 Mar 8.

Authors

Greta Pintacuda^{1

2

3}, Yu-Han H Hsu^{1

2

4}, Kalliopi Tsafou^{1

4}, Ka Wan Li⁵, Jacqueline M Martín^{1

3}, Jackson Riseman^{1

3}, Julia C Biagini^{1

2}, Joshua K T Ching^{1

2}, Daya Mena^{1

2}, Miguel A Gonzalez-Lozano⁵, Shawn B Egri⁶, Jake Jaffe⁶, August B Smit⁵, Nadine Fornelos^{1

2

4}, Kevin C Eggan^{1

3}, Kasper Lage^{1

2

4

7}

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁴ Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Department of Molecular and Cellular Neurobiology, CNCR, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands.
⁶ Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, 4000 Roskilde, Denmark.

Abstract

Autism spectrum disorders (ASDs) have been linked to genes with enriched expression in the brain, but it is unclear how these genes converge into cell-type-specific networks. We built a protein-protein interaction network for 13 ASD-associated genes in human excitatory neurons derived from induced pluripotent stem cells (iPSCs). The network contains newly reported interactions and is enriched for genetic and transcriptional perturbations observed in individuals with ASDs. We leveraged the network data to show that the ASD-linked brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and to characterize a PTEN-AKAP8L interaction that influences neuronal growth. The IGF2BP1-3 complex emerged as a convergent point in the network that may regulate a transcriptional circuit of ASD-associated genes. Our findings showcase cell-type-specific interactomes as a framework to complement genetic and transcriptomic data and illustrate how both individual and convergent interactions can lead to biological insights into ASDs.

Keywords: IP-MS; autism spectrum disorders; exome sequencing; induced excitatory neurons; protein-protein interactions.

Abstract

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