Proteinopathy in inflammatory neurodegeneration

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Inflammatory neurodegeneration drives disability progression in multiple sclerosis (MS), an incurable and debilitating condition that arises early in adult life and represents an enormous health and socioeconomic burden. An enigmatic finding in MS is the early neuronal loss and inexorable progression of neurodegeneration. However, a gap in understanding MS pathogenesis exists about the inflammatory-induced neuronal alterations that propagate neuronal demise. Our recent study of the previous funding period, examining neuron-specific response profiles in reaction to inflammation, revealed that neuroinflammation leads to the induction and toxic deposition of proteins in neuronal somata in mice and humans. Thus, we propose a novel model for inflammatory neurodegeneration, in which inflammation induces a neuronal response network resulting in intracellular deposition of aggregation-prone proteins that disturb neuronal physiology, spread to adjacent cells and are thereby responsible for progressive neurodegeneration. This study mechanistically explores this model 1) by profiling the proteome of inflamed neurons in vivo and by characterising the topological network of deposited proteins thereby devising a ‘disease module’; 2) by investigating the inflammatory driven activity and solubility of aggregation-prone proteins and their interaction with the proteasome degradation pathway; 3) by identifying whether protein accumulations spread from cell-to-cell and by probing the possibility to therapeutically interfere. Overall, using transgenic mouse models, proteomics, cell culture and human tissue, this project will deliver a systematic unravelment of how neuronal degeneration is initiated, regulated and propagated by a proteinopathic ‘disease module’ in neuroinflammation. It has the chance to change the conceptual approach of neuroprotective treatment strategies in MS and other neurodegenerative diseases associated with neuroinflammation.