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Generation of Native, Untagged Huntingtin Exon1 Monomer and Fibrils Using a SUMO Fusion Strategy
Published on: June 27, 2018
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Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted
J Mario Isas1, Nitin K Pandey1, Hui Xu1
1Department of Physiology & Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Nature Communications
|July 14, 2021
Summary
Huntington's disease protein aggregates (HTTex1 fibrils) show varying toxicity due to proline-rich domain dynamics. Less entangled, more toxic fibrils enhance protein interactions and seeding in neurodegenerative disease.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Huntington's disease (HD) is linked to the huntingtin protein (HTTex1) forming toxic cross-β fibrils.
- The C-terminal proline-rich domain (PRD) of HTTex1 influences fibril structure and toxicity.
Purpose of the Study:
- To investigate the structural basis for varying HTTex1 fibril toxicity.
- To understand the role of PRD dynamics and entanglement in fibril formation and seeding.
Main Methods:
- Analysis of HTTex1 fibril structures and dynamics.
- In vitro seeding assays with recombinant HTTex1.
- Cell-based assays to assess HTTex1 aggregation and toxicity.
Main Results:
- HTTex1 fibrils exhibit varying toxicity correlated with PRD entanglement and dynamics.
- Fibril strains are interconvertible, with the polyQ core structure remaining constant.
- Less entangled, more toxic fibrils show increased affinity for protein interactors and enhanced seeding.
Conclusions:
- PRD structure and dynamics at the fibril surface modulate seeding and protein interactions.
- These mechanisms contribute to the toxicity of HTTex1 aggregates in neurodegenerative disease.
- Understanding these structural variations offers insights into HD pathogenesis.
