Protein clumps can cause brain diseases

Prion protein cross-seeding deactivates TDP-43.

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Neurodegenerative diseases involve clumped proteins in the brain, leading to cell death. While the link between protein clumps and cell death is apparent, how misfolded proteins cause it is unknown. Professor Jörg Tatzelt’s team at Ruhr University Bochum found that misfolded prion proteins can deactivate TDP-43, a crucial protein for maintaining balance, especially in nerve cells. 

TDP-43 dysfunction is linked to diseases like ALS and dementia. These findings, published in Brain on September 5, 2023, are vital for understanding neurodegenerative disease mechanisms.

Neurodegenerative diseases like Alzheimer’s, Parkinson’s dementia, and prion diseases have various causes. However, they share a common factor—misfolded proteins forming deposits in the brain. Research led by Jörg Tatzelt highlights the crucial role of misfolded proteins in these diseases. 

There’s an ongoing debate about the harmful protein types and how they damage particular neurons. Studies on disease-related genes suggest two ways misfolded proteins contribute to neurodegeneration: they can become toxic or lose their normal function, disrupting essential cell processes.

Jörg Tatzelt explains, “The assumption used to be that the misfolding of a specific protein characterized every neurodegenerative disease. However, it has been shown that misfolded proteins produced more frequently in one disease can also induce the aggregation of other proteins, a mechanism referred to as cross-seeding.”

TDP-43 is a protein that helps make proteins in nerve cells and maintains their balance in patients with diseases like ALS or dementia, TDP-43 clumps in the brain. Prion protein misfolding causes diseases like Creutzfeldt-Jakob. Current research suggests misfolded prion proteins become toxic, but we only partially understand how they cause nerve cell death.

Prion proteins, when misfolded, can make TDP-43 lose its normal function. Researchers used various methods, including cell cultures and brain samples from Creutzfeldt-Jakob patients, to show that misfolded prion proteins cause TDP-43 to clump and become inactive. 

This interaction leads to cell-forming aggregates, reducing TDP-43’s regular activity and changing protein expression. The study suggests that prion proteins and TDP-43 work together in neurodegenerative diseases. Brain samples from some Creutzfeldt-Jakob patients showed TDP-43 aggregates and prion protein deposits, revealing a new way prion proteins can affect normal signaling pathways through cross-seeding.

In conclusion, misfolded prion proteins can lead to neurodegenerative diseases by causing the clumping and inactivation of TDP-43. This interaction alters physiological signaling pathways, reducing TDP-43’s normal function and contributing to the development of such diseases.

Journal reference:

  1. Stella A Polido, Cristiana Stuani, et al., Cross-seeding by prion protein inactivates TDP-43. Brain. DOI: 10.1093/brain/awad289.

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