Browsing by Author "Misgeld, Thomas"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss during Neuromuscular Synapse Elimination
    (Elsevier, 2016-11-23) Brill, Monika S.; Kleele, Tatjana; Ruschkies, Laura; Wang, Mengzhe; Marahori, Natalia A.; Reuter, Miriam S.; Hausrat, Torben J.; Weigand, Emily; Fisher, Matthew; Ahles, Andrea; Engelhardt, Stefan; Bishop, Derron L.; Kneussel, Matthias; Misgeld, Thomas; Department of Cellular & Integrative Physiology, IU School of Medicine
    Developmental axon remodeling is characterized by the selective removal of branches from axon arbors. The mechanisms that underlie such branch loss are largely unknown. Additionally, how neuronal resources are specifically assigned to the branches of remodeling arbors is not understood. Here we show that axon branch loss at the developing mouse neuromuscular junction is mediated by branch-specific microtubule severing, which results in local disassembly of the microtubule cytoskeleton and loss of axonal transport in branches that will subsequently dismantle. Accordingly, pharmacological microtubule stabilization delays neuromuscular synapse elimination. This branch-specific disassembly of the cytoskeleton appears to be mediated by the microtubule-severing enzyme spastin, which is dysfunctional in some forms of upper motor neuron disease. Our results demonstrate a physiological role for a neurodegeneration-associated modulator of the cytoskeleton, reveal unexpected cell biology of branch-specific axon plasticity and underscore the mechanistic similarities of axon loss in development and disease.
  • Thumbnail Image
    Item
    Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model
    (SpringerNature, 2016-11-16) Romanelli, Elisa; Merkler, Doron; Mezydlo, Aleksandra; Weil, Marie-Theres; Weber, Martin S.; Nikic, Ivana; Potz, Stephanie; Meinl, Edgar; Matznick, Florian E.H.; Kreutzfeldt, Mario; Ghanem, Alexander; Conzelmann, Karl-Klaus; Metz, Imke; Bruck, Wolfgang; Routh, Matthew; Simons, Mikael; Bishop, Derron; Misgeld, Thomas; Kerschensteiner, Martin; Department of Cellular & Integrative Physiology, IU School of Medicine
    Oligodendrocyte damage is a central event in the pathogenesis of the common neuroinflammatory condition, multiple sclerosis (MS). Where and how oligodendrocyte damage is initiated in MS is not completely understood. Here, we use a combination of light and electron microscopy techniques to provide a dynamic and highly resolved view of oligodendrocyte damage in neuroinflammatory lesions. We show that both in MS and in its animal model structural damage is initiated at the myelin sheaths and only later spreads to the oligodendrocyte cell body. Early myelin damage itself is characterized by the formation of local myelin out-foldings-'myelinosomes'-, which are surrounded by phagocyte processes and promoted in their formation by anti-myelin antibodies and complement. The presence of myelinosomes in actively demyelinating MS lesions suggests that oligodendrocyte damage follows a similar pattern in the human disease, where targeting demyelination by therapeutic interventions remains a major open challenge.