Kanazawa University NanoLSI Podcast: Biomolecular insights into protein-insolubility-related disease

Transcript of this podcast

Hello and welcome to the NanoLSI podcast. Thank you for joining us today. In this episode we feature the latest research by Rikinari Hanayama from the Kanazawa University NanoLSI and colleagues. 

The research described in this podcast was published in the Frontiers in Molecular Biosciences in March 2022.

Learn more about their research here: WPI Kanazawa Nano Life Science Institute

https://nanolsi.kanazawa-u.ac.jp/en/research/researchers/

Reference

Hiroki Yamaguchi, Hironori Kawahara, Noriyuki Kodera, Ayanori Kumaki, Yasutake Tada, Zixin Tang, Kenji Sakai, Kenjiro Ono, Masahito Yamada, and Rikinari Hanayama.

Extracellular Vesicles Contribute to the Metabolism of Transthyretin Amyloid in Hereditary Transthyretin Amyloidosis, Front. Mol. Biosci. 9, 839917 (2022).

DOI: 10.3389/fmolb.2022.839917

URL: https://doi.org/10.3389/fmolb.2022.839917

Biomolecular insights into protein-insolubility-related disease

Researchers at Kanazawa University elucidate how small bio-containers enclosed by membranes are involved in a disease called ATTRv amyloidosis.  

Amyloidosis is the collective name for a group of diseases characterized by the deposition of amyloids — insoluble proteins that form due to the misfolding and aggregation of soluble proteins — outside of cells.  Such depositions lead to cellular dysfunctions, and take place in patients with Alzheimer’s disease, Parkinson’s disease and dementia.  

In the disease called hereditary (variant) transthyretin amyloidosis (abbreviated ATTRv amyloidosis), variants of the transthyretin (TTR) gene lead to TTR amyloid deposits in several organs, with symptoms including muscle weakness and cardiac failure.  

It is known that the removal of amyloid proteins is promoted by so-called extracellular vesicles (EVs) — small ‘biocontainers’ enclosed by a membrane — but what is unclear is whether EVs are involved in the formation and subsequent deposition of TTR amyloids in the context of ATTRv amyloidosis. 

 Rikinari Hanayama and colleagues from Kanazawa University have now studied the relationship between ATTRv amyloidosis and EVs, and confirm that the latter play an important role in the aggregation and deposition of TTR amyloids.

The researchers first analyzed the serum of ATTRv amyloidosis patients for traces of TTR amyloid.  (Serum is blood without the clotting factors.)  They found that TTR is present in EVs derived from serum, and that the so-called V30M mutation variant of TTR aggregates at the membranes of serum-derived EVs.

Hanayama and colleagues then looked at what happened when V30M-TTR amyloids were added to cell cultures, with and without serum-derived EVs.  They found that V30M-TTR amyloid aggregates are deposited on cells in a much more pronounced way when serum-derived EVs are present, indicating that serum-derived EVs promote the aggregation of V30M-TTR and their deposition on cells.

From a comparison between ATTRv amyloidosis patients and healthy individuals, the scientists found that ATTRv amyloidosis is associated with a lower amount of TTR aggregates in serum-derived EVs.  

The hypothesis that emerges from the experiments is that in ATTRv amyloidosis patients, the presence of V30M-TTR and EVs leads to a self-enhancing uptake of EVs; this then leads to an enhanced deposition of TTR aggregates in tissue, resulting in a decrease of TTR aggregates in serum.

The findings of Hanayama and colleagues suggest that TTR in serum-derived EVs is a potential target for both ATTRv amyloidosis diagnosis and therapy.  The researchers also point to the relevance of their results on our understanding of Alzheimer’s disease because TTR inhibits the nucleation of

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