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Study uncovers mechanisms of protein misfolding linked to neurodegenerative diseases


Nonpolar and amyloidogenic core fragments are modular in tau fibrils. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-36572-3
Nonpolar and amyloidogenic core fragments are modular in tau fibrils. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-36572-3

Protein misfolding is a crucial aspect of several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. Understanding the mechanisms behind this misfolding is essential for identifying new treatments for these diseases. A team at UT Southwestern has developed a computational approach to analyze the structure of amyloid fibrils, which are made up of misfolded proteins associated with neurodegenerative diseases. The study published in Nature Communications offers key insights into the mechanisms of protein misfolding.


Background


Misfolded proteins are normally soluble proteins that have assembled in a way that makes them insoluble and dangerous to the brain. Amyloids are a type of misfolded proteins that are associated with several neurodegenerative diseases. Tau proteins play a crucial role in healthy brain cells, but when they misfold, they expose certain motifs that allow them to self-replicate and build on themselves, leading to the formation of aggregated tau proteins that cause "tauopathies." Tauopathies are associated with several neurodegenerative diseases, including Alzheimer's and chronic traumatic encephalopathy.



Computational Approach


The researchers at UT Southwestern developed a computational approach to estimate the energetics of interactions in structures of amyloid fibrils. They used tau as a model protein and applied the approach to 27 distinct tau protein structures to uncover networks of interactions involved in stabilizing different amyloid fibril folds. The researchers also used this information to classify different tauopathies based on fibril structure conformation. This classification opens the door to designing tau sequences that only adopt a single conformation, which could lead to new treatments for neurodegenerative diseases.


Impact


The study is believed to be the first to computationally model the effect of mutations on fibril structure stability. This insight is crucial in developing methods to predict these structures from the protein sequence alone. The computational approach developed by the researchers could also be applied to control folding of other amyloid-forming proteins that direct normal biological processes to manipulate them.


Journal Information: Vishruth Mullapudi et al, Network of hotspot interactions cluster tau amyloid folds, Nature Communications (2023). DOI: 10.1038/s41467-023-36572-3
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