Monday, May 12, 2025
5/12/2025
Pathogenic mechanisms of PACS2 syndrome variant in developing neurons - Project Summary Neurodevelopmental disorders (NDDs) are heterogenous and usually present with complex etiology. Individuals with these conditions present cognitive impairment accompanied by lifelong deficits; yet remarkably little is known about their neurological basis. To develop effective treatments, it is imperative to understand the dysregulation of molecular and cellular processes leading to these conditions. PACS2 syndrome is a NDD characterized by epilepsy, intellectual disability, craniofacial abnormalities, and hypotonia. PACS2 syndrome results from a recurrent de novo c.625G>A variant in the gene encoding Phosphofurin Acidic Cluster Sorting protein 2 (PACS2) resulting in a Glutamate to Lysine (p.E209K) substitution. PACS2 encodes a multifunctional sorting protein that mediates protein trafficking between the endomembrane system which includes the ER, Golgi, mitochondria, lysosomes, and the plasma membrane. The mechanism of PACS2 syndrome is relatively understudied, however, a recent report found that PACS2 p.E209K has an increased half-life compared to WT PACS2. They also found an increased association of PACS2 p.E209K with 14-3-3ε, and that cells overexpressing PACS2 p.E209K or 14-3-3ε undergo apoptosis. Given that PACS2 function has rarely been studied in neurons or model organisms and the neuronal-specific effect of the p.E209K variant are not known. Here, we will use patient-derived and CRISPR knock-in induced pluripotent stem cell (iPSC) models to study the molecular and neuronal-specific deficits associated which PACS2 p.E209K. We hypothesize that neurons carrying the PACS2 p.E209K substitution present with increased susceptibility to apoptosis via the lysosomal pathway. We will test this hypothesis by addressing whether PACS2 p.E209K promotes apoptosis, precocious neural differentiation and hyperexcitability in neurons (aim 1) by increasing PACS2 stability and PACS2- mediated recruitment of pro-apoptotic proteins to the lysosomes in neurons (aim 2). Results from this proposal will greatly enhance our understanding of the mechanisms by which PACS2 p.E209K affects developing neurons. Moreover, we will uncover mechanisms by which PACS2 in general and PACS2 p.E209K in particular, regulate pro-apoptotic pathways. Finally, results from this proposal will contribute to our knowledge of disease mechanisms for PACS2 Syndrome, which may reveal therapy targets.
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