Preprint A foundational atlas of autism protein interactions reveals molecular convergence, 2023, Wang et al.

A foundational atlas of autism protein interactions reveals molecular convergence
Belinda Wang; Rasika Vartak; Yefim Zaltsman; Zun Zar Chi Naing; Kelsey M Hennick; Benjamin J Polacco; Ali Bashir; Manon Eckhardt; Mehdi Bouhaddou; Jiewei Xu; Nawei Sun; Micaela Lasser; Yuan Zhou; Keelan Z Guiley; Una Chan; Julia A Kaye; Prachi Khare; Sam Drake; Vanessa Drury; David F Burke; Silvano Gonzalez; Sahar Alkhairy; Montana Morris; Tierney Baum; Rebecca Krasnoff; Sheng Wang; Presley Pham; Juan Arbalaez; Dexter Pratt; Shivali Chag; Thomas Rolland; Thomas Bourgeron; Steven Finkbeiner; Sourav Bandyopadhay; Trey Ideker; Pedro Beltrao; Helen Rankin Willsey; Kirsten Obernier; Tomasz J Nowakowski; Ruth Huttenhain; Matthew W State; A. Jeremy Willsey; Nevan J Krogan

Despite the identification of a large number of high-confidence (hc) autism spectrum disorder (ASD) risk genes, translation to viable treatment targets remains elusive.

Using affinity purification-mass spectrometry and HEK293T cells, we constructed a protein-protein interaction (PPI) network involving 100 hcASD risk genes, revealing over 1,800 PPIs, the vast majority of which have not been previously described. Importantly, the interactors are highly expressed in the human brain and neural progenitor cells, and enriched for ASD, but not schizophrenia, genetic risk. The network is highly connected, converges on protein complexes, including those involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification.

We also generated a PPI map using over 50 patient-derived missense variants to identify differential physical interactions. Using these data, we leveraged AlphaFold2 predictions to prioritize direct PPIs as well as specific variants for interrogation in Xenopus tropicalis and human forebrain organoids.

One such mutation in the transcription factor FOXP1, which disrupts interaction with FOXP4, led to a reconfiguration of DNA binding sites and disruption of neurogenesis, with a particularly strong impact on deep layer cortical and subplate neurons,consistent with a large body of work in ASD.

Overall, this work offers critical new insights into molecular mechanisms underlying ASD that results from large effect genetic variants and describes a powerful platform to develop and test novel therapeutic strategies for a wide range of genetically-defined conditions.


Link | PDF (Preprint: BioRxiv)

 

FOXP4 was recently found to be associated with long covid.

 

See also this preprint from UCSF —

Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis
Nawei Sun; Noam Teyssier; Belinda Wang; Sam Drake; Meghan Seyler; Yefim Zaltsman; Amanda Everitt; Nia Teerikorpi; Helen Rankin Willsey; Hani Goodarzi; Ruilin Tian; Martin Kampmann; Jeremy Willsey

Recent studies have identified over one hundred high confidence (hc) autism spectrum disorder (ASD) genes. Systems biological and functional analyses on smaller subsets of these genes have consistently implicated excitatory neurogenesis. However, the extent to which the broader set of hcASD genes are involved in this process has not been explored systematically nor have the biological pathways underlying this convergence been identified.

Here, we leveraged CROP-Seq to repress 87 hcASD genes in a human in vitro model of cortical neurogenesis. We identified 17 hcASD genes whose repression significantly alters developmental trajectory and results in a common cellular state characterized by disruptions in proliferation, differentiation, cell cycle, microtubule biology, and RNA-binding proteins (RBPs). We also characterized over 3,000 differentially expressed genes, 286 of which had expression profiles correlated with changes in developmental trajectory.

Overall, we uncovered transcriptional disruptions downstream of hcASD gene perturbations, correlated these disruptions with distinct differentiation phenotypes, and reinforced neurogenesis, microtubule biology, and RBPs as convergent points of disruption in ASD.


Link | PDF (Preprint: BioRxiv)

 

To borrow a relevant meme...

Biopsychosocial screeching

 

I had to look that one up but yes, very relevant.