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

## TL;DR

This study shows how PCSK9 loss disrupts neural tube development by affecting a protein pathway, leading to birth defects in the nervous system.

## Contribution

The study identifies a novel PCSK9-regulated LIN28A/HES5/JMY pathway involved in neural tube defects.

## Key findings

- PCSK9 loss causes incomplete neural tube structures and microfilament network disruption in neural progenitor cells.
- PCSK9 promotes LIN28A degradation via lysosomal pathways, which regulates HES5 and JMY expression.
- JMY overexpression in zebrafish increases the severity of neural tube defects associated with PCSK9 loss.

## Abstract

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.

PCSK9 acts as a molecular chaperone promoting LIN28A lysosomal degradation. LIN28A elevates transcription factor HES5, increasing JMY expression. PCSK9 loss causes neural tube defects (NTDs) by disrupting the LIN28A/HES5/JMY axis, and high JMY disorganizes the neural progenitor cell microfilament network, leading to incomplete neural tube structure in organoids. This pathway reveals novel mechanisms and therapeutic targets for NTDs.