Related Experiment Video
Updated: Jul 17, 2025
12:57
Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
16.0K
Cross-seeding by prion protein inactivates TDP-43
Stella A Polido1, Cristiana Stuani2, Aaron Voigt3
1Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801 Bochum, Germany.
Brain : a Journal of Neurology
|September 5, 2023
Summary
Misfolded prion protein (PrP) aggregates can trigger the clumping and inactivation of TAR DNA-binding protein-43 (TDP-43), disrupting neuronal function and contributing to neurodegeneration in prion diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Protein aggregate accumulation is common in neurodegenerative diseases.
- Prion diseases involve neurodegeneration caused by misfolded prion protein (PrP).
- The mechanism by which pathogenic PrP affects neuronal viability is not fully understood.
Purpose of the Study:
- To investigate how misfolded prion protein (PrP) conformers interfere with neuronal viability.
- To elucidate the interaction between PrP and TAR DNA-binding protein-43 (TDP-43).
Main Methods:
- In vitro protein aggregation assays.
- Cell culture experiments.
- Analysis of animal models and human brain samples.
Main Results:
- Misfolded PrP induces aggregation and inactivation of TDP-43.
- PrP aggregates interact with TDP-43, promoting its conversion into non-dynamic assemblies.
- Cytosolic mislocalized PrP sequesters TDP-43, decreasing TDP-43-dependent splicing and altering protein expression.
- Cytosolic TDP-43 aggregates were observed in neurons of relevant models and patients.
Conclusions:
- Aberrant PrP conformers can impair neuronal function through cross-seeding of TDP-43 aggregation.
- This study reveals a novel mechanism linking PrP pathology to TDP-43 dysfunction in neurodegeneration.
Related Concept Videos
03:03Amyloid Fibrils
9.6K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
9.6K
01:37The Unfolded Protein Response
4.7K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.7K
01:29Subviral Agents
41
Subviral agents are infectious entities that resemble viruses but lack one or more viral components, such as a capsid or essential replication machinery. These agents include viroids, prions, and satellites, each possessing distinct structural and functional characteristics that influence their mode of infection and replication.Viroids are the simplest subviral agents, consisting of circular, single-stranded RNA molecules without a protein coat. They exclusively infect plants, relying entirely...
41
02:28Leaky Scanning
5.2K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.2K