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.