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PolyQ-Expanded Mutant Huntingtin Forms Inclusion Body Following Transient Cold Shock in a Two-Step Aggregation
Ana Raquel Castro E Costa1, Sachin Mysore1, Praneet Paruchuri1
1Department of Cell Biology and Neuroscience, Nelson Biology Laboratory, Rutgers State University of New Jersey, 604 Allison Road, Piscataway, New Jersey 08854, United States.
ACS Chemical Neuroscience
|December 27, 2022
Summary
Cold shock rapidly induces mutant Huntingtin protein aggregation into inclusion bodies in cells. This process involves protein structuring and rigidification, independent of microtubules or new protein synthesis.
Area of Science:
- Cell Biology
- Neuroscience
- Biochemistry
Background:
- Protein aggregate formation is a key feature of neurodegenerative diseases.
- Understanding the cell chemistry driving mutant Huntingtin (mHtt) protein aggregation into inclusion bodies (IBs) is crucial.
Purpose of the Study:
- To investigate the mechanisms by which a transient cold shock (CS) induces mHtt protein aggregation.
- To explore the role of cell chemistry and protein dynamics in the formation of mHtt IBs.
Main Methods:
- Utilized an inducible cell model of Huntington's disease.
- Applied a transient cold shock (4 °C) followed by recovery incubation (25-37 °C).
- Assessed the impact of sodium chloride and urea on IB formation.
Main Results:
- Transient cold shock rapidly induced the compaction of diffuse mHtt into cytosolic inclusion bodies.
- CS-induced IB formation was independent of microtubule integrity and de novo protein synthesis.
- Sodium chloride accelerated, while urea suppressed IB formation.
Conclusions:
- Cold shock constrains mHtt conformation, facilitating de-solvation and hydrophobic interactions for IB formation.
- mHtt structuring and rigidification are primary drivers of IB formation via H-bond-mediated cross-linking.
- This suggests a two-step mechanism for mHtt IB formation in living cells.
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