Seeing Beyond the Fibril: Why the Amyloid Microenvironment Matters

This is the authors' abstract. We don't add key points for this paper.

Neurodegenerative diseases rob the memory, mobility, and independence of millions globally. A hallmark of neurodegeneration is the aggregation of misfolded proteins, known as amyloids. Following Alzheimer’s and Parkinson’s disease, transthyretin amyloidosis (ATTR) is the third most prominent amyloid disease, originating from transthyretin (TTR), a 55 kDa tetrameric thyroxine carrier protein. Amyloid formation in ATTR begins with the dissociation of TTR-tetramers, followed by partial monomer denaturation, non-native TTR oligomerization, and ultimately formation of amyloid aggregates. While physiological TTR and isolated amyloids have been studied extensively, the interaction of amyloids with the extracellular matrix (ECM) remains poorly defined. Our cryo-EM data of ex vivo amyloid extracts from ATTR patients are selectively enriched in Collagen VI (COLVI), a major component of the ECM. Using a combination of single-particle analysis and sub-tomogram averaging revealed the formation of co-filaments between TTR amyloids and COLVI, matching earlier co-fibrils of light-chain amyloids and COLVI [1], supporting a structured amyloid microenvironment. Amyloid decoration by ECM components may provide a structural basis for the existing hypothesis for why the clearance of amyloids through phagocytosis is inhibited [2]. Not only does the amyloidogenic state of TTR interact with COLVI, but our in-vitro data demonstrates a strong delay of amyloid formation in the presence of COLVI when using ATTR risk-variants of soluble TTR. This protective effect of ECM components to delay amyloidogenesis could explain why previously reported ECM dysregulation leads to increased amyloid deposition [3]. Overall, our findings offer new routes to accelerate the development of anti-amyloid drugs by targeting their interaction with ECM components.