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Quantifying misfolded protein oligomers as drug targets and biomarkers in Alzheimer and Parkinson diseases

Abstract

Protein misfolding and aggregation are characteristic of a wide range of neurodegenerative disorders, including Alzheimer and Parkinson diseases. A hallmark of these diseases is the aggregation of otherwise soluble and functional proteins into amyloid aggregates. Although for many decades such amyloid deposits have been thought to be responsible for disease progression, it is now increasingly recognized that the misfolded protein oligomers formed during aggregation are, instead, the main agents causing pathological processes. These oligomers are transient and heterogeneous, which makes it difficult to detect and quantify them, generating confusion about their exact role in disease. The lack of suitable methods to address these challenges has hampered efforts to investigate the molecular mechanisms of oligomer toxicity and to develop oligomer-based diagnostic and therapeutic tools to combat protein misfolding diseases. In this Review, we describe methods to quantify misfolded protein oligomers, with particular emphasis on diagnostic applications as disease biomarkers and on therapeutic applications as target biomarkers. The development of these methods is ongoing, and we discuss the challenges that remain to be addressed to establish measurement tools capable of overcoming existing limitations and to meet present needs.

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Fig. 1: Protein oligomers are diverse and present at different concentrations and different locations in healthy and diseased individuals.
Fig. 2: Immunoassays to detect and quantify misfolded protein oligomers.
Fig. 3: Fluorescence microscopy methods to detect and quantify misfolded protein oligomers.
Fig. 4: Biosensors detect and quantify misfolded protein oligomers.
Fig. 5: Other methods to detect and quantify misfolded protein oligomers.

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Acknowledgements

This work was supported by the UK Medical Research Council. P.S. is supported by a Royal Society University Research Fellowship (URF\R1\201461).

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Kulenkampff, K., Wolf Perez, AM., Sormanni, P. et al. Quantifying misfolded protein oligomers as drug targets and biomarkers in Alzheimer and Parkinson diseases. Nat Rev Chem 5, 277–294 (2021). https://doi.org/10.1038/s41570-021-00254-9

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