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Highly Potent Peptide Therapeutics To Prevent Protein Aggregation in Huntington's Disease
Anooshay Khan1,2, Cemile Elif Özçelik1, Ozge Begli1
1UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, 06800 Ankara, Turkey.
Insights
Huntington's disease (HD) therapies are advanced by new peptide drugs. These peptides inhibit the formation of toxic protein aggregates linked to mutant Huntingtin (mHtt) protein, offering a promising therapeutic lead.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin (Htt) gene.
- Expanded repeats lead to mutant Htt (mHtt) protein fragments that misfold and aggregate in the brain, driving disease progression.
Purpose of the Study:
- To identify and evaluate peptide-based inhibitors for blocking mHtt protein aggregation.
- To explore peptide therapeutic leads for delaying Huntington's disease progression.
Main Methods:
- Screening of inhibitory peptides against monomeric wild-type (Htt(Q25)) and mutant (Htt(Q46), Htt(Q103)) Huntingtin fragments.
- Utilizing Thioflavin T (ThT) assay to monitor fibril kinetics.
- Employing atomic force microscopy (AFM) to visualize the impact of peptides on fibril formation.
Main Results:
- Selected peptides demonstrated significant suppression of fibril formation in mutant Huntingtin proteins.
- Peptides effectively inhibited the aggregation of mHtt fragments in vitro.
- Atomic force microscopy confirmed the peptides' ability to disrupt aggregate formation.
Conclusions:
- Peptide-based inhibitors show potential in preventing the aggregation of mutant Huntingtin proteins.
- These findings support the development of peptide therapies to slow Huntington's disease progression.
- The identified peptides represent a viable therapeutic lead for further optimization.
Abstract:
Huntington's disease (HD) is a neurodegenerative disorder resulting from a significant amplification of CAG repeats in exon 1 of the Huntingtin (Htt) gene. More than 36 CAG repeats result in the formation of a mutant Htt (mHtt) protein. These amino-terminal mHtt fragments lead to the formation of misfolded proteins, which then form aggregates in the relevant brain regions. Therapies that can delay the progression of the disease are imperative to halting the course of the disease. Peptide-based drug therapies provide such a platform. Inhibitory peptides were screened against monomeric units of both wild type (Htt(Q25)) and mHtt fragments, Htt(Q46) and Htt(Q103). Fibril kinetics was studied by utilizing the Thioflavin T (ThT) assay. Atomic force microscopy was also used to study the influence of the peptides on fibril formation. These experiments demonstrate that the chosen peptides suppress the formation of fibrils in mHtt proteins and can provide a therapeutic lead for further optimization and development.
