Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers.

Özgür Genç,Giulia Zunino,Richard D Fetter,Yelena Kulik,Graeme W Davis,Stephan J Sanders,Joon-Yong An

doi:10.7554/elife.55775

Özgür Genç, Giulia Zunino + Show 5 more

Open Access

https://doi.org/10.7554/elife.55775

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Journal: eLife	Publication Date: Jul 1, 2020
Citations: 17	License type: CC BY 4.0

Affiliation: University of California, San Francisco, Korea University

Abstract

We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (RIMS1, CHD8, CHD2, WDFY3, ASH1L) causing a common failure of presynaptic homeostatic plasticity (PHP) in Drosophila. Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, PHP is sensitized and rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first known heterozygous mutations that commonly genetically interact with multiple ASD gene orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, PDPK1 and PPP2R5D, are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of CREG, a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, we define a novel genetic landscape by which diverse, unrelated autism risk genes may converge to commonly affect the robustness of synaptic transmission.

Highlights

Autism Spectrum Disorder (ASD) is a polygenic disorder with a complex underlying genetic etiology (Bourgeron, 2015)
The five ASD gene orthologs were chosen to reflect a broad range of biological activities that are associated with the numerous ASD-associated genes identified to date
Systematic screening of the phenotypically normal population has identified individuals that are resistant to the effects of well-established, debilitating disease causing mutations, an effect termed ‘resilience’ that is attributed to the effects of genetic context (Chen et al, 2016; Friend and Schadt, 2014)

Summary

Introduction

Autism Spectrum Disorder (ASD) is a polygenic disorder with a complex underlying genetic etiology (Bourgeron, 2015). Even in cases where a rare de novo mutation confers risk for ASD, additional processes are likely to contribute to the ASD phenotype (Leppa et al, 2016; Peter et al, 2019) including the engagement of adaptive physiological mechanisms (Gaugler et al, 2014; Gibson, 2009; Hartman et al, 2001; Hou et al, 2019; Kitano, 2007; Plomp et al, 1992; Sackton and Hartl, 2016; Sardi and Gasch, 2018; Bourgeron, 2015). Homeostatic plasticity, in particular, has garnered considerable attention as an adaptive physiological process that might be relevant to the phenotypic penetrance of ASD mutations (Antoine et al, 2019; Bourgeron, 2015; Mullins et al, 2016; Nelson and Valakh, 2015; Ramocki and Zoghbi, 2008).

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