Polyglutamine-Specific Gold Nanoparticle Complex Alleviates Mutant Huntingtin-Induced Toxicity

Area of Science:

• Biomedical Engineering
• Neuroscience
• Nanotechnology

Background:

• Huntington's disease (HD) is a protein misfolding disorder characterized by mutant huntingtin (mHtt) protein aggregates.
• The aggregation of polyglutamine (polyQ)-rich mHtt is implicated in neuronal toxicity and dysfunction.

Purpose of the Study:

• To design and synthesize a polyglutamine-specific gold nanoparticle (AuNP) complex to target and alleviate mHtt toxicity.
• To evaluate the efficacy of the AuNP complex in dissociating mHtt aggregates and reducing neurotoxicity in vitro and in vivo.

Main Methods:

• Synthesis of polyglutamine-specific AuNPs by decorating AuNPs with an amphiphilic peptide (JLD1).
• Development of a cell-penetrating complex (AuNPs-JLD1-PEI) by integrating polyethyleneimine (PEI).
• Assessment of aggregate dissociation, β-sheet content reduction, cellular uptake, mHtt binding, and functional improvement in HD models.

Main Results:

• AuNPs-JLD1 dissociated polyQ aggregates and reduced β-sheet content in a concentration-dependent manner.
• AuNPs-JLD1-PEI penetrated cells, bound cytosolic mHtt, dissociated inclusions, reduced oligomers, and ameliorated mHtt-induced toxicity.
• The complex showed brain transport and improved functional outcomes in an HD Drosophila larva model.

Conclusions:

• The combination of AuNPs, JLD1 peptides, and cell-penetrating polymers is feasible for targeting mHtt aggregation and oligomerization.
• This approach offers potential as an early therapeutic strategy for Huntington's disease.