Developmental functions of organelle contact sites in axonal morphogenesis

• Applicants: Dr. Margret Bülow; Professor Dietmar Schmucker, Ph.D.
• Subject Area: Developmental Neurobiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535112684

The formation and plasticity of synapses are critical processes that determine the functionality of a neuron. Multiple factors determine synaptogenesis in axons, such as the availability of membrane components. Organelles are specialized subcellular structures, many of which are required for protein modification and quality control. One important organelle involved in protein biosynthesis is the endoplasmic reticulum (ER). In somatic cells, the ER forms contact sites with many other organelles, e.g. mitochondria, to regulate membrane trafficking, lipid synthesis, organelle biogenesis, redox homeostasis and protein turnover. How organelle contacts influence synaptogenesis is incompletely understood. In the highly polarized neurons, different mechanisms and requirements for organelle contact regulation might apply. Disturbed organelle function in neurons is underlying neurodegenerative diseases such as Parkinson’s disease (PD). We have identified an ER protein, Creld, which is required for functional ER-mitochondria contact sites. In the absence of Creld, mitochondrial dynamics are impaired, and unfunctional contacts block the activity of respiratory complex I. The resulting redox imbalance impairs the function of dopaminergic neurons and causes a strong, PD-like locomotion defect. In this proposal we show that loss of Creld in single neurons induces dramatic synapse overgrowth and link it to ER-mitochondria contact formation. By combining our expertises on organelle communication, axon branching and synaptogenesis, and employing ultrastructural and super-resolution microscopy, we want to define the role of organelle contacts in neuron morphogenesis and function.

• DFG Programme: Research Grants