PCSK9 Loss‐of‐Function Disrupts Cellular Microfilament Network via LIN28A/HES5/JMY Axis in Neural Tube Defects

Neural tube defects (NTDs) are complex multigenic disorders and are the most prevalent and severe congenital malformations that affect the central nervous system. PCSK9 is identified as a molecular marker for the prenatal diagnosis of NTDs during its early stages in fetuses; however, its role in NTD neurulation and pathogenesis remains unclear. This study introduces PCSK9 knockout embryonic stem cells (ESCs) into neural organoid (NO) and neural progenitor cell (NPC) models and finds that PCSK9 loss leads to an incomplete neural tube structure in NOs and microfilament network disorder in NPCs. Transcriptome sequencing analysis shows that PCSK9 loss induces NTDs via the key molecule JMY. JMY overexpression in a zebrafish model increased the incidence and severity of PCSK9 loss-associated NTDs. Mechanistically, PCSK9 acts as a molecular chaperone that promotes LIN28A degradation via the lysosomal pathway. LIN28A is an RNA-binding protein that affects JMY expression by regulating the transcription factor HES5. Thus, PCSK9 loss disrupts the cellular microfilament network via the LIN28A/HES5/JMY axis, leading to NTDs. These findings provide important insights into the pathogenesis and therapeutics of NTDs.