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Updated: Apr 30, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Biodegradable delivery system containing a peptide inhibitor of polyglutamine aggregation: a step toward therapeutic
Abhayraj S Joshi1, Ashwani Kumar Thakur
1Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, Uttar Pradesh, 208016, India.
Insights
We developed nanoparticles to deliver a peptide inhibitor for polyglutamine aggregation, a key factor in Huntington's disease (HD). These nanoparticles successfully inhibited protein aggregation in vitro, offering a potential therapeutic strategy for HD.
Area of Science:
- Neuroscience
- Biotechnology
- Drug Delivery
Background:
- Huntington's disease (HD) and other neurodegenerative disorders stem from CAG repeat expansion mutations, leading to toxic polyglutamine protein aggregation.
- Inhibiting polyglutamine aggregation is a promising therapeutic avenue, but peptide inhibitors face challenges like in vivo degradation and blood-brain barrier (BBB) penetration.
Purpose of the Study:
- To synthesize and characterize poly-d,l-lactide-co-glycolide (PLGA) nanoparticles encapsulating a polyglutamine aggregation inhibitor peptide (PGQ9).
- To evaluate the in vitro release kinetics of the PGQ9 peptide from the nanoparticles.
- To assess the efficacy of PGQ9-loaded nanoparticles in inhibiting the aggregation of a model Huntingtin protein peptide.
Main Methods:
- Nanoprecipitation was used to synthesize PLGA nanoparticles containing the PGQ9 peptide.
- Characterization involved infrared spectroscopy and HPLC assays to confirm PGQ9 presence within the nanoparticles.
- In vitro release kinetics were studied to understand degradation and diffusion mechanisms.
- The inhibitory effect on aggregation was tested using an aggregation-prone Q35 P10 peptide.
Main Results:
- Spherical nanoparticles (<200 nm) with uniform distribution were successfully synthesized.
- PGQ9 peptide was confirmed to be present within the synthesized nanoparticles.
- Nanoparticles demonstrated controlled release of PGQ9 via erosion and diffusion.
- PGQ9-loaded nanoparticles effectively arrested the elongation phase of Q35 P10 peptide aggregation.
Conclusions:
- This study presents the first successful synthesis of PLGA nanoparticles encapsulating a polyglutamine aggregation inhibitor peptide (PGQ9).
- The developed nanoparticles show controlled release of the active peptide and demonstrate in vitro efficacy in inhibiting polyglutamine aggregation.
- These findings represent a significant first step towards developing nanoparticle-mediated delivery systems for peptide inhibitors targeting polyglutamine diseases like HD.
Abstract:
Huntington's and eight other neurodegenerative diseases occur because of CAG repeat expansion mutation culminating into an expanded polyglutamine tract in respective protein. In Huntington's disease (HD), a number of CAG repeats beyond normal repeat length (>36) lead to the formation of mutant protein, the proteolytic cleavage of which induces aggregation in polyglutamine length-dependent manner. The neurodegeneration in this disease is linked to aggregation, and its inhibition is a potential approach for therapeutic development. Although peptides and other molecules have been developed for inhibiting aggregation, peptides in general are susceptible to degradation in vivo conditions. To understand their clinical significance, they also need to be delivered through blood-brain barrier. Here, for the first time, we have synthesized poly-d,l-lactide-co-glycolide nanoparticles containing a polyglutamine aggregation inhibitor peptide PGQ9 [P(2) ], by nanoprecipitation method. This process yielded less than 200 nm spherical nanoparticles with uniform distribution. Characterization studies by infrared spectroscopy-based and HPLC-based assays show the presence of PGQ9 [P(2) ] in nanoparticles. In vitro release kinetics demonstrates that nanoparticles release PGQ9 [P(2) ] by erosion and diffusion processes. When the PGQ9 [P(2) ]-loaded nanoparticles are incubated with aggregation-prone Q35 P10 peptide, representing N-terminal part of Huntingtin protein, it arrests the elongation phase of Q35 P10 aggregation. These findings propose the first step toward delivery of a peptide inhibitor against polyglutamine aggregation in HD.
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