Determining Disease Mechanisms of PACS1 Syndrome ASD Using iPSC-Derived Models

Rylaarsdam, Lauren Elizabeth

doi:https://doi.org/10.21985/n2-6fbb-qe15

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Determining Disease Mechanisms of PACS1 Syndrome ASD Using iPSC-Derived Models

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Autism spectrum disorder (ASD) and intellectual disability (ID) are two of the most highly prevalent neurodevelopmental disorders (NDDs), each affecting roughly 2% of the population. Despite the need for therapies, few exist due to a myriad of challenges, such as the complex underlying genetic etiology and historic inaccessibility of neural tissue. In certain instances, the genetic origin of an NDD can be traced to a single gene, providing a more constrained model to study these disorders and work towards therapy development. This thesis presents some of the first work investigating disease mechanisms of one such ID resulting from a single recurrent de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1) called PACS1 syndrome. PACS1 is known to play roles in the endosomal pathway and nucleus, but the impact of the variant on developing neurons had never been investigated, leaving patients with few therapeutic options. Here we use stem cell-derived models to show that young PACS1(+/R203W) neurons have a transient propensity towards GABAergic differentiation. This population is not maintained in mature PACS1(+/R203W) neurons although they have a higher density of GABAergic synapses. PACS1(+/R203W) mature neurons aberrantly express genes enriched for synaptic signaling processes, which is functionally manifested as a prolonged network burst duration resulting from an increased inter-spike interval and a multimodal bursting pattern. This suggests that an aberrant regulation of ionic flux affecting spike frequency underlies the neurological phenotypes experienced by patients. Our work is the first to investigate the impact of p.R203W PACS1 on developing human neural tissue, revealing electrophysiological mechanisms of disease and putative targets for pharmacological intervention. In addition to paving the way for PACS1 syndrome therapies, this work contributes to a body of research from diverse ASD and ID cases that could eventually reveal more ubiquitous therapy targets.

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