RNA-targeted therapy corrects neuronal deficits in PACS1 syndrome mice

Neurodevelopmental disorders (NDDs) are frequently associated with dendritic abnormalities in pyramidal neurons that affect arbor complexity, spine density, and synaptic communication (1,2). The underlying genetic causes are often complex, obscuring the molecular pathways that drive these disorders (3). Next-generation sequencing has identified recurrent de novo missense mutations in a handful of genes associated with NDDs, offering a unique opportunity to decipher the molecular pathways (4). One such gene is PACS1, which encodes the multi-functional trafficking protein PACS1 (or PACS-1); a single recurrent de novo missense mutation, c607C>T (PACS1(R203W)), causes developmental delay and intellectual disability (ID) (5,6). The processes by which PACS1(R203W) causes PACS1 syndrome are unknown, and there is no curative treatment. We show that PACS1(R203W) increases the interaction between PACS1 and the α-tubulin deacetylase HDAC6, elevating enzyme activity and appropriating control of its posttranscriptional regulation. Consequently, PACS1(R203W) reduces acetylation of α-tubulin and cortactin, causing the Golgi to fragment and enter developing neurites, leading to increased dendrite arborization. The dendrites, however, are beset with diminished spine density and fewer functional synapses, characteristic of ID pathology. Treatment of PACS1 syndrome mice with PACS1- or HDAC6-targeting antisense oligonucleotides restores neuronal structure and synaptic transmission, suggesting PACS1(R203W)/HDAC6 may be targeted for treating PACS1 syndrome neuropathology.