Emmy Noether P 3. Phase: Imaging neuroinflammatory axonal injury at nanoscale resolution

01/02/2021 to 31/01/2022

Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults. Current therapies are effective in modulating inflammatory phases of the disease, but cannot stop progressive phases. As the main pathological correlate of the progressive neurological disability is axonal injury, a deeper understanding of how axons are damaged in MS will enable the development of new therapies. I have previously identified a novel form of axonal injury, focal axonal degeneration (FAD). In vivo imaging showed that FAD is a sequential process, characterized by intermediate stages that are stable and can even spontaneously recover. Reversibility is important, as it suggests the existence of a therapeutic window of opportunity. However, this process is very poorly understood at the molecular level, and we do not know what determines if axons will recover or degenerate. We also do not know what mediates initial axonal changes. To address this, I will study the primary sites of injury, nodes of Ranvier, and analyze how their architecture is changed in neuroinflammatory conditions. Furthermore, I aim to characterize the dynamic changes in the axonal shape, and the contribution of the cytoskeleton and membrane shaping proteins to it, and their relevance for FAD reversibility. These questions will be studied in a mouse model of multiple sclerosis. In parallel, I will develop a suitable in vitro system that will offer defined control over the onset of injury. To decipher molecular changes at the nanoscale level and correlate them to the stages of axonal injury, I aim to use super-resolution microscopy. This will be complemented with novel genetic code expansion tools for engineering of fluorescent labels to maximize the strength and generality of the method and improve resolution. This will offer a unique perspective to unravel molecular FAD mechanisms and provide an innovative toolbox to study neuroinflammatory processes.