Macromolecular crowding in solution alters huntingtin interaction and aggregation at interfaces

Area of Science:

• Neurodegenerative diseases
• Biochemistry
• Cell biology

Background:

• Huntington's disease (HD) is a fatal neurodegenerative disorder.
• It is caused by an expanded polyglutamine (polyQ) in the huntingtin protein (htt).
• Toxic htt aggregates, including fibrils and oligomers, form due to polyQ expansion.

Purpose of the Study:

• To investigate the impact of macromolecular crowding on htt aggregation.
• To study htt aggregation in bulk solution and at solid/liquid or membrane/liquid interfaces.
• To understand how crowding affects htt interaction with different surfaces.

Main Methods:

• Used dextran, Ficoll, and polyethylene glycol (PEG) as crowding agents.
• Investigated htt aggregation in bulk solution.
• Utilized in situ atomic force microscopy (AFM) to track htt aggregation at mica and bilayer interfaces.

Main Results:

• Crowding enhanced heterogeneity of non-fibrillar htt aggregates in solution.
• Crowding suppressed htt fibril deposition on mica interfaces.
• Crowding enhanced htt aggregate deposition on supported lipid bilayers, altering their morphology.

Conclusions:

• Macromolecular crowding significantly influences htt aggregation at interfaces.
• The effect of crowding depends on the type of interface (e.g., mica vs. lipid bilayer).
• Crowding alters htt aggregation pathways and the nature of the resulting aggregates.