On the slow lane: Studying the Mechanisms underlying the slow axonal transport of cytoplasmic and cytoskeletal proteins in vivo

• Applicant: Dr. Oliver Vinzenz Glomb
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562903099

The enormous length of axons mandates specialized transport mechanisms to distribute proteins to their site of action to build and maintain a functional neuronal network. Consequently, conditions that perturb axonal transport routes impair axon growth and function resulting in an early onset of neurodegeneration. Cytoskeletal and cytoplasmic proteins account for the major transported protein mass in axons that are transported in a common transport mechanism known as slow axonal transport. Although slow axonal transport is the main axonal transport mechanism, it remains poorly understood. The high abundance and ubiquitous presence of slow axonal transported proteins throughout the entire axon prevent the use of conventional fluorescent labelling approaches to visualize transport events, dampening mechanistic insights. Our long-term goal is to close this gap and understand how the transport of cytoplasmic and cytoskeletal proteins contributes to neuronal function in health and disease. We recently developed a temporally controlled labelling approach that allowed us to visualize the transport the slow axonal transport route of a cytoskeletal protein, α-spectrin, for the first time directly by fluorescence microscopy in neurons of the living nematode Caenorhabditis elegans and identified first molecular components of its transport machinery. In the scope of this proposal, we will i) gain a deeper mechanistic understanding about the regulatory mechanisms of this transport route by using α-spectrin transport as a proxy, ii) determine common regulatory principles of this transport route by applying our labelling strategy to other cytoskeletal and cytoplasmic proteins and iii) decipher how this transport route contributes to neuronal growth, by using our advantage of visualizing and manipulating slow axonal transport inside a living animal. Our results will provide novel insights into a poorly characterized, yet central transport route in neurons and its role in neuronal health and disease. Many slow axonal transported cargos such as Tau, α-synuclein or dynein are directly linked to neurodegenerative diseases, so that we expect that this proposal will also generate ample research avenues beyond the scope of this proposal for the establishment of our new working group.

• DFG Programme: Emmy Noether Independent Junior Research Groups