Title:SynB3 Conjugated QBP1 Passes Blood-Brain Barrier Models and Inhibits PolyQ Protein Aggregation
Volume: 29
Issue: 1
Author(s): Lingyan Zuo, Weiqian Li, Jifang Shi, Yingzhen Su, Hongyan Shuai*Xin Yu*
Affiliation:
- School of Basic Medical Sciences, Dali University, Dali, China
- Institute of Translational Medicine for Metabolic
Diseases, Dali University, Dali, China
Keywords:
Aggregation, cell penetrating peptide, polyglutamine, QBP1, blood brain barrier models, huntington protein.
Abstract: Background: Polyglutamine diseases are degenerative diseases in the central nervous
system caused by CAG trinucleotide repeat expansion which encodes polyglutamine tracts, leading
to the misfolding of pathological proteins. Small peptides can be designed to prevent polyglutamine
diseases by inhibiting the polyglutamine protein aggregation, for example, polyglutamine
binding peptide 1(QBP1). However, the transportation capability of polyglutamine binding peptide
1 across the blood-brain barrier is less efficient. We hypothesized whether its therapeutic effect
could be improved by increasing the rate of membrane penetration.
Objective: The objective of the study was to explore whether polyglutamine binding peptide 1 conjugated
cell-penetrating peptides could pass through the blood-brain barrier and inhibit the aggregation
of polyglutamine proteins.
Methods: In order to investigate the toxic effects, we constructed a novel stable inducible PC12
cells to express Huntington protein that either has 11 glutamine repeats or 63 glutamine repeats to
mimic wild type and polyglutamine expand Huntington protein, respectively. Both SynB3 and
TAT conjugated polyglutamine binding peptide 1 was synthesized, respectively. We tested their capabilities
to pass through a Trans-well system and subsequently studied the counteractive effects
on polyglutamine protein aggregation.
Results: The conjugation of cell-penetrating peptides to SynB3 and TAT enhanced the transportation
of polyglutamine binding peptide 1 across the mono-cell layer and ameliorated polyglutamine--
expanded Huntington protein aggregation; moreover, SynB3 showed better delivery efficiency
than TAT. Interestingly, it has been observed that polyglutamine binding peptide 1 specifically inhibited
polyglutamine-expanded protein aggregation rather than affected other amyloidosis proteins,
for example, β-Amyloid.
Conclusion: Our study indicated that SynB3 could be an effective carrier for polyglutamine binding
peptide 1 distribution through the blood-brain barrier model and ameliorate the formation of polyglutamine
inclusions; thus SynB3 conjugated polyglutamine binding peptide 1 could be considered
as a therapeutic candidate for polyglutamine diseases.
