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Mechanisms of Developmental and Injury-related Axon Branch Loss

Mid-Term Report Summary - DIABLO (Mechanisms of Developmental and Injury-related Axon Branch Loss)

The DIABLo project aims to compare the mechanisms by which neuronal processes (axons) dismantle in development and disease. This process is essential for normal development of the nervous system but appears to be reactivated during neurological diseases, such as neurodegeneration and neuroinflammation. How this process is initiated and regulated, however, is poorly understood. We are taking advantage of two relatively simple parts of the mammalian nervous system – peripheral motor axons and axons in the spinal cord, to study these questions. To date (half-way through its funding), DIABLo has generated the following major results:
• During development, the microtubular cytoskeleton in branches of axons that are remodelling is locally destabilized. The cytoskeleton, a network of protein filaments, is necessary to maintain the stability of cells and their appendages, but also to mediate transport and signaling. Notably, the developmental destabilization of the cytoskeleton seems to depend partially on a neurodegeneration-related enzyme, spastin – as it is known that if the spastin gene is mutated in humans, a severe neurodegenerative disease of the motor system ensues. This work has hence revealed parallels between physiological and pathological axon dismantling.
• In parallel to destabilization of the cytoskeleton inside remodelling axon, also the further maturation of axon-glial interactions is delayed locally on such axon branches, especially the formation of myelin. This is important, as both processes – axon remodelling and myelin formation – need to be carefully coordinated to ensure proper formation of neural circuits. Currently we are exploring the mechanisms by which myelination on not-yet stabilized axon branches is regulated.
• During various forms of spinal pathology (spinal contusion and local inflammation-mediated damage), several parallel pathways of axon dismantling seem to be engaged. Notably, some of these pathways seem to involve reversible intermediate states that could be targets for intervention. How these pathways relate to each other and physiological programs of axon remodelling and dismantling is currently our focus.