Of the four major macromolecules of life –proteins, sugars, lipids, and nucleic acids– only lipids are inherently hydrophobic. This means lipids cannot move freely through our body, including within our own cells; and their distribution must be facilitated. Many types of lipids are heterogeneously distributed across various organelles of the cell. While vesicular trafficking transports lipids in bulk between organelles, non-vesicular trafficking of lipids plays a key role in defining the lipid compositions of organelles. This non-vesicular trafficking of lipids is achieved by a group of lipid transfer proteins that carry lipids using their hydrophobic cavities. As of 2025, there are about 100 intracellular lipid transfer proteins identified in humans and the function of many lipid transfer proteins in defining cellular levels and distributions remains unclear. In this project, we combine genetic and analytical tools to identify the function of unknown lipid transfer proteins, followed by biochemical and structural biology characterisation of their molecular mechanisms of action.
Lipid transfer proteins typically function by interacting with two organelles, defining the source and destination of the lipids they transport. Most of these proteins rely on binding to the VAPA and VAPB proteins on the endoplasmic reticulum (ER). Mutations in the VAPB gene have been identified in familial cases of amyotrophic lateral sclerosis (ALS), and reduced levels of VAPB protein have also been observed in sporadic ALS patients. Because VAPB is essential for correct localization of lipid transfer proteins to the ER, its dysfunction disrupts lipid homeostasis. This project aims to investigate how ALS-linked VAPB mutations affect intracellular lipid organization and homeostasis. We use CRISPR/Cas9-based genomic editing tools in cultured and induced pluripotent stem cells to study the effect of the ALS-causing VAPB variants. Although VAPB mutations account for only a small subset of familial ALS cases, lipid imbalance is increasingly recognized as a common feature across multiple neurodegenerative diseases.
Our research is supported by Maastricht University, ALS Stichting, and the EU-MSCA Doctoral Network LipidBright
Maastricht University | M4i – Maastricht Multimodal Molecular Imaging Institute