Charge within Nt17 peptides modulates huntingtin aggregation and initial lipid binding events

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Huntington's disease (HD) is linked to toxic aggregation of the huntingtin protein (htt).
• The N-terminal 17 amino acids (Nt17) of htt play a role in its aggregation and interaction with lipid membranes.
• Nt17 can form amphipathic alpha-helices, promoting htt oligomerization and htt/lipid interactions.

Purpose of the Study:

• To investigate the impact of post-translational modifications (PTMs) on Nt17's aggregation and lipid binding properties.
• To understand how acetylation and phosphorylation at specific sites within Nt17 affect htt aggregation and membrane interactions.

Main Methods:

• Utilized free Nt17 peptides with point mutations mimicking acetylation or phosphorylation.
• Incubated modified Nt17 peptides with htt-exon1(46Q) to assess fibril formation and oligomer morphology.
• Examined peptide/lipid complexation and interactions using lipid vesicles.

Main Results:

• Nt17 peptides mimicking acetylation or phosphorylation reduced fibril formation of htt-exon1(46Q).
• These modifications altered the morphology of htt oligomers.
• Changes in peptide/lipid complexation were observed upon exposure to lipid vesicles.
• Oligomers containing modified Nt17 showed reduced interactions with lipids.

Conclusions:

• Post-translational modifications of Nt17 significantly influence huntingtin protein aggregation and lipid binding.
• Modulating Nt17 acetylation and phosphorylation offers a potential therapeutic strategy for Huntington's disease by affecting htt aggregation and membrane interactions.