Presynaptic dysfunction inCASK-related neurodevelopmental disorders

Abstract

HighlightsModelling of CASK-related disorders using iPSC-derived human neuronal cells CASK mutations cause dysregulation of its protein interactor partners Reduced CASK levels primarily affect inhibitory presynapse development In vitro GABAergic phenotype predicts in vivo neurotransmitter levels Summary (150 words)CASK-related disorders are a genetically defined group of neurodevelopmental syndromes.There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK mutation consequences and neuronal level effects using induced pluripotent stem cell-derived neurons from two mutation carriers; one male diagnosed with ASD and a female with MICPCH. We show a reduction of the CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of gene sets involved in presynaptic development and CASK protein interactors. Furthermore, CASKdeficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in brain. Our data shows that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy and periventricular calcifications

“…1,6,7 In line with this is the observation that liprin-β1 forms a ternary complex with liprin-α2 and CASK, 3 a presynaptic scaffolding protein essential for neurodevelopment. 8,9 A previous knock-out model of the PPFIBP1 homolog hlb-1 in C. elegans showed abnormal locomotion behavior. Furthermore, abnormal and decreased distribution of snb-1, an ortholog of human VAMPfamily proteins involved in presynaptic vesicle release, increased presynaptic zone size and resistance to the acetylcholinesterase inhibitor aldicarb indicated a role of hlb-1 in the regulation of presynaptic function.…”

Loss of Neurodevelopmental Gene CASK Disrupts Neural Connectivity in Human Cortical Excitatory Neurons

“…Interestingly, a decrease in inhibitory synaptic puncta density was seen in iPSC-neurons derived from ASD CASK mutation carrier (Becker et al, 2020). These studies altogether show that E-I balance could potentially be disrupted in CASK LOF in human cells.…”

“…Mechanistically, the observed E-I imbalance is attributed in part to NMDARs, as re-expression of NR2b restores the E-I balance (Mori et al, 2019). Interestingly, a decrease in inhibitory synaptic puncta density was seen in iPSC-neurons derived from ASD CASK mutation carriers (Becker et al, 2020). Altogether, these studies show that E-I balance could potentially be disrupted in CASK LOF in human cells.…”

“…This defect was primarily rescued by restoring GluN2B, suggesting a postsynaptic mechanism (Mori et al, 2019). In comparison, human iPSC-neurons derived from two different patients carrying CASK mutations reveal some deficits in inhibitory presynaptic puncta size in one patient background (Becker et al, 2020). However, due to heterogeneity in patient genetic background, sex, and nature of CASK mutations, patient iPSC-derived neuronal studies require multiple lines and proper controls.…”

Crystal Structure of Caskin1/CASK complex reveals the molecular basis of the binding specificity of CASK_CAMK domain and its binding partners

“…Even reducing CASK expression will impair synaptic function [16]. In humans, CASK-related disorders are not limited by neurodevelopmental syndromes, such as X-lined mental retardation, microcephaly, and autism [17][18][19]. Cooperating with other scaffold proteins, like discs-large homolog 1 (DLG1), CASK also plays a critical role in kidney development [20].…”