A novel role for ABCA2 in cholesterol homeostasis

• Applicant: Professor Dr. Arne Möller
• Subject Area: Structural Biology ; Biochemistry ; Biophysics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569268081

Cholesterol is a primary lipid in vertebrates, increasing the stability and fluidity of the plasma membrane, while it is only present in relatively low amounts in intracellular bilayers. Moreover, cholesterol is the precursor for steroid hormones and bile acids, executing vital functions in the body. Especially in the brain, large amounts of cholesterol are required, not only for insulating the axons through the myelin sheaths. The blood-brain barrier uncouples cholesterol metabolism and homeostasis in the brain from the remaining body, prohibiting cholesterol uptake from the bloodstream. Additionally, cholesterol in the brain exhibits a vastly extended lifetime, while only small cholesterol fractions are degraded, secreted, and synthesized, respectively. In combination, limited uptake, low de-novo synthesis, and long lifetime require effective recycling and maintenance mechanisms for cholesterol homeostasis in the brain. Our preliminary data suggests a direct involvement of the ABC transporter ABCA2 in cholesterol trafficking and homeostasis. Its cellular localization in late endosomes and lysosomes and its crucial role in intracellular cholesterol transport and lipid homeostasis distinguish it from ABCA1. However, the cellular function of ABCA2 and its exact role, as well as its structure, is currently unknown. Our proposal aims to elucidate the structure and molecular mechanisms of ABCA2. More ambitiously, we propose a direct and undescribed role of ABCA2 in cholesterol recycling in the lysosome.

• DFG Programme: Research Grants