Final Report Summary - NEMESIS (Neuroprotection in Multiple Sclerosis: From Molecular Imaging to Screenable Models)
Multiple sclerosis (MS) is common neurological disease that affects more than 2.5 million people worldwide and often leads to severe disability. Disability in this disease is caused by immune cells that enter the brain and spinal cord and there damage the connections between individual nerve cells (the so-called “axons”). Here we want to better understand how these axons are attacked by immune cells and develop new therapeutic strategies that can prevent such nervous system damage. For this purpose we have established new in vivo microscopy techniques that allow us to directly visualize how cellular, subcellular and molecular alterations of nerve cell connections are initiated in the intact nervous system. These techniques enable us, for example, to follow an important cell biological function of axons, the transport of organelles, as well as the activation of key effector mechanisms of nerve cell damage such as oxidative stress or the influx of calcium ions. We have first established and validated these techniques in “simpler” models of nervous system injury caused e.g. by spinal trauma and then transfered them to the more complex cellular interactions that lead to axon injury in neuroinflammatory lesions.
Our analysis of the functional state of axons identified a pervasive state of axonal dysfunction in neuroinflammatory lesions that precedes structural alterations of the axon. This early and widespread axonal dysfunction is of particular interest for multiple sclerosis for two reasons. First, such transient dysfunction of structurally intact axons could explain why disease symptoms in the early relapsing-remitting stage of the disease can occur but also recover quickly. Second, while short-lasting transport deficits that we observe in acute MS models likely have little permanent consequences, transport deficits persist in chronic neuroinflammatory lesions that characterize the progressive stage of MS. We can further show that these persistent transport deficits lead to the depletion of vital energy producing organelles (so called “mitochondria”) in the distal parts of the axon – a process that can contribute to the axonal and synaptic dystrophy observed in advanced stages of MS. This study thus illustrates how the dynamic analysis of experimental neuroinflammatory lesions can yield new insights that can be translated to multiple sclerosis. Furthermore by imaging calcium changes in axons we could show that the intraaxonal accumulation of calcium ions drives inflammatory axon degeneration and pinpoint novel sites for therapeutic interventions. Taken together this project has thus improved our understanding of the mechanisms that underlie axon degeneration, revealed the functional implications of the degeneration process and identified new targets that can help preventing it.
Our analysis of the functional state of axons identified a pervasive state of axonal dysfunction in neuroinflammatory lesions that precedes structural alterations of the axon. This early and widespread axonal dysfunction is of particular interest for multiple sclerosis for two reasons. First, such transient dysfunction of structurally intact axons could explain why disease symptoms in the early relapsing-remitting stage of the disease can occur but also recover quickly. Second, while short-lasting transport deficits that we observe in acute MS models likely have little permanent consequences, transport deficits persist in chronic neuroinflammatory lesions that characterize the progressive stage of MS. We can further show that these persistent transport deficits lead to the depletion of vital energy producing organelles (so called “mitochondria”) in the distal parts of the axon – a process that can contribute to the axonal and synaptic dystrophy observed in advanced stages of MS. This study thus illustrates how the dynamic analysis of experimental neuroinflammatory lesions can yield new insights that can be translated to multiple sclerosis. Furthermore by imaging calcium changes in axons we could show that the intraaxonal accumulation of calcium ions drives inflammatory axon degeneration and pinpoint novel sites for therapeutic interventions. Taken together this project has thus improved our understanding of the mechanisms that underlie axon degeneration, revealed the functional implications of the degeneration process and identified new targets that can help preventing it.