Abstract
The pathological hallmark of misfolded protein diseases and aging is the accumulation of proteotoxic aggregates. However, the mechanisms of proteotoxicity and the dynamic changes in fiber formation and dissemination remain unclear, preventing a cure. Here we adopted a reductionist approach and used atomic force microscopy to define the temporal and spatial changes of amyloid aggregates, their modes of dissemination and the biochemical changes that may influence their growth. We show that pre-amyloid oligomers (PAO) mature to form linear and circular protofibrils, and amyloid fibers, and those can break reforming PAO that can migrate invading neighbor structures. Simulating the effect of immunotherapy modifies the dynamics of PAO formation. Anti-fibers as well as anti-PAO antibodies fragment the amyloid fibers, however the fragmentation using anti-fibers antibodies favored the migration of PAO. In conclusion, we provide evidence for the mechanisms of misfolded protein maturation and propagation and the effects of interventions on the resolution and dissemination of amyloid pathology.
Highlights
Bernini, Fabrizio, Daniele Malferrari, Marcello Pignataro, Carlo Augusto Bortolotti, Giulia Di Rocco, Lidia Lancellotti, Maria Franca Brigatti, et al 2016
We show that pre-amyloid oligomers (PAO) mature to form linear and circular protofibrils, and amyloid fibers, and those can break reforming PAO that can migrate invading neighbor structures
Tapping mode (TM) topography images showed, at 1-24 hrs, pseudo spherical PAO that increased over time in number and size (Fig. 2b–d)
Summary
Fabrizio, Daniele Malferrari, Marcello Pignataro, Carlo Augusto Bortolotti, Giulia Di Rocco, Lidia Lancellotti, Maria Franca Brigatti, et al 2016. The mechanisms of proteotoxicity and the dynamic changes in fiber formation and dissemination remain unclear, preventing a cure. Major obstacles in the therapeutic approach to proteinopathies include the identification of the toxic amyloid-related entities, the still unclear nature of the mechanisms of proteotoxicity, and the dynamic changes in the process of amyloid fiber formation and dissemination. We aimed at defining the temporal and spatial dynamic changes of misfolded protein aggregation and fibrillogenesis, and their modes of dissemination. This is important because identifying how amyloid develops and the steps from misfolded proteins to fibrillar formation, expansion and metastasis will allow tailoring our interventions to each of the different maturation and propagation stages. The ultimate goal would be to interfere with the key mechanisms responsible for the development, progression and/or exacerbation of the organs damage and block them
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