PACS1 syndrome mutation disrupts dynein-mediated cargo transport via HDAC6 and BICD2.

PACS1 syndrome is a neurodevelopmental disorder caused by a recurrent heterozygous missense mutation in PACS1 (p.R203W). We previously showed that PACS1(R203W) aberrantly potentiates HDAC6 activity, leading to Golgi fragmentation and neuronal deficits through an unresolved mechanism (Villar-Pazos and Thomas et al., Nature Commun. 14:6547-6564 (2023)). Here, we identify cytoplasmic dynein-1 heavy chain (DHC1) as a PACS1 interactor essential for maintaining furin localization at the trans-Golgi network. PACS1(R203W) induces a dynein loss-of-function phenotype that disrupts furin trafficking and Golgi organization. We demonstrate that PACS1(R203W)-HDAC6 recruits the adaptor BICD2, forming a complex that disperses the Golgi and impairs dynein function. Cargo motility assays revealed that PACS1(R203W) reduces dynein initiation frequency and velocity, defects rescued by HDAC6 inhibition or by expressing the dynein regulator Lis1. These findings uncover a pathogenic mechanism in which PACS1(R203W)-HDAC6-BICD2 disrupts dynein-driven transport, placing PACS1 syndrome within the broad spectrum of microtubule trafficking disorders.