Spreading proteins in neurodegeneration: where do they take us?

Abstract

The ‘prion-like’ nature of neurodegenerative diseases has been mooted for a number of years. The central concept is of self-propagating misfolded proteins spreading from neuron to neuron, associated with more or less stereotypical patterns of neurodegeneration in specific diseases. Apart from prion protein (PrP) in the archetypal prion diseases, the evidence that amyloid-β, tau, and now—in this issue of Brain —α-synuclein, all propagate through the brain is compelling, with implications for the pathogenesis of Alzheimer’s disease, frontotemporal dementias and other tauopathies, and Parkinson’s disease. The spread of neurodegenerative diseases through protein misfolding thus appears to be a truly generic phenomenon. Why does this matter and where does it take us? The inescapable fact of neurodegenerative diseases is that we currently have no effective way of treating them. However, the more we learn about pathogenesis, the more likely we are to identify therapeutic approaches that could succeed. So how does the spreading protein hypothesis help us? Will inhibiting cell-to-cell transmission of these pathological conformers prevent neurodegeneration? Importantly, what is the connection between spread of proteins and actual neurodegeneration? The study by Masuda-Suzukake et al. (2013) goes beyond confirming the place of α-synuclein on the list of self-propagating proteins. It raises interesting questions about the link—or lack of it—between transmission of pathological proteins and their neurotoxic effects. The relationship between toxicity and ‘infectivity’ is an important phenomenon in prion and other protein misfolding disorders. Increasing our insights into this is likely to inform our approach to understanding and treating these diseases. …