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Related Concept Videos

Huntington Disease l: Introduction01:21

Huntington Disease l: Introduction

Huntington disease or HD is a progressive, fatal neurodegenerative disorder inherited in an autosomal dominant pattern.PathophysiologyIt is caused by expansion of the CAG trinucleotide repeat in the HTT gene on chromosome 4 (4p16.3), producing an abnormal huntingtin protein with an expanded polyglutamine tract. This misfolded protein disrupts cellular function, leading to neuronal death. Normal alleles have ≤26 repeats, 27–35 are intermediate (risk of expansion), 36–39 show reduced penetrance,...

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Related Experiment Video

Updated: Jun 13, 2026

Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
10:52

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Published on: December 10, 2021

Lipid Composition Drives Mutant Huntingtin Dimerization and Membrane Association: Insights from Computational

Catalin Nicoara1, Emanuele Criscuolo2, Angela De Cristofaro3

  • 1Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00121 Rome, Italy.

Molecules (Basel, Switzerland)
|June 12, 2026
PubMed
Summary

Huntington's disease involves mutant huntingtin protein misfolding and dimerization. Cholesterol in neuronal membranes promotes this dimeric protein's aggregation, suggesting cholesterol modulation as a potential therapeutic strategy for HD.

Keywords:
cholesterol-dependent modulationmolecular dynamicsmutant huntingtin exon 1neurodegenerative diseasespolyglutamine misfoldingprotein dimerizationprotein–membrane interactions

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Related Experiment Videos

Last Updated: Jun 13, 2026

Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
10:52

Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System

Published on: December 10, 2021

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
07:08

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species

Published on: February 27, 2018

Generation of Native, Untagged Huntingtin Exon1 Monomer and Fibrils Using a SUMO Fusion Strategy
11:22

Generation of Native, Untagged Huntingtin Exon1 Monomer and Fibrils Using a SUMO Fusion Strategy

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Computational Biology

Background:

  • Huntington's disease (HD) is a neurodegenerative disorder linked to mutant huntingtin (mHTT) protein with expanded polyglutamine (polyQ) tracts.
  • Aberrant protein folding, aggregation, and membrane interactions of mHTT are key to HD pathogenesis.
  • Understanding the early molecular events driving mHTT toxicity is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the structural properties, dimerization, and membrane interactions of mHTT with 70 polyQ repeats (mHTT-Q70) using molecular dynamics (MD) simulations.
  • To explore the role of membrane lipid composition, particularly cholesterol, in mHTT-Q70 aggregation and membrane association.
  • To identify potential therapeutic targets for HD by understanding the interplay between mHTT structure and neuronal membranes.

Main Methods:

  • Utilized molecular dynamics (MD) simulations to analyze the structural dynamics and α-helical content of mHTT-Q70.
  • Employed coarse-grained MD simulations to assess the dimerization propensity of mHTT-Q70.
  • Simulated interactions between mHTT-Q70 and model neuronal membranes with varying cholesterol concentrations.

Main Results:

  • mHTT-Q70 exhibits partially structured α-helical conformations and increased polyQ domain flexibility, predisposing it to misfolding.
  • mHTT-Q70 shows a strong tendency to dimerize, suggesting oligomerization as an early step in aggregation.
  • Cholesterol dose-dependently enhanced the association of dimeric mHTT-Q70 with neuronal membranes, while monomeric mHTT-Q70 showed minimal binding.
  • Specific membrane lipids like phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine differentially modulated mHTT-Q70 binding.

Conclusions:

  • The study highlights a dynamic interplay between polyQ-driven misfolding, dimerization, and membrane lipid composition in HD pathogenesis.
  • Cholesterol-dependent membrane binding of dimeric mHTT-Q70 suggests membrane composition, especially cholesterol levels, is a critical factor in early mHTT aggregation and toxicity.
  • Modulating membrane composition, particularly cholesterol, presents a novel therapeutic avenue for Huntington's disease treatment.