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Monitoring Protein Aggregation Kinetics In Vivo using Automated Inclusion Counting in Caenorhabditis elegans
Published on: December 17, 2021
Aggregation kinetics of interrupted polyglutamine peptides.
Robert H Walters1, Regina M Murphy
1Department of Chemical and Biological Engineering, University of Wisconsin, Madison, 1415 Engineering Drive, Madison, WI 53706, USA.
Journal of Molecular Biology
|August 9, 2011
Summary
Inserting specific residues into polyglutamine peptides alters protein aggregation. Proline residues yield soluble aggregates, while (D)PG insertion accelerates fibril formation, challenging existing aggregation models.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Expanded polyglutamine domains are implicated in neurodegenerative diseases like Huntington's disease.
- Protein aggregation, driven by polyglutamine expansion, is linked to neurotoxicity.
- Synthetic peptides offer a model to study polyglutamine aggregation mechanisms.
Purpose of the Study:
- To investigate how interrupting residues affect the conformational and aggregation properties of polyglutamine peptides.
- To elucidate the mechanism of polyglutamine aggregation.
Main Methods:
- Insertion of alanine, proline, or a (D)PG β-turn template into Q20 polyglutamine peptides.
- Examination of peptide conformational changes and aggregation kinetics.
- Analysis of aggregate morphology and alignment.
Main Results:
- Alanine insertion resulted in fibrillar aggregates similar to native Q20.
- Proline insertion led to soluble, non-maturing aggregates.
- (D)PG insertion rapidly accelerated aggregation into less aligned fibrils.
Conclusions:
- Polyglutamine aggregation involves initial monomer association into soluble oligomers, followed by slow structural rearrangement into sedimentable aggregates.
- The (D)PG insert's effect contradicts a simple nucleation-elongation model, suggesting a different aggregation pathway.
- Soluble oligomers are dynamic, while insoluble aggregates are relatively inert.
