title: Inhibition of Aggregation of Mutant Huntingtin by Nucleic Acid Aptamers In Vitro and in a Yeast Model of Huntington's Disease.
abstract: Elongated polyglutamine stretch in mutant huntingtin (mhtt) correlates well with the pathology of Huntington's disease (HD). Inhibition of aggregation of mhtt is a promising strategy to arrest disease progression. In this work, specific, high-affinity RNA aptamers were selected against monomeric mhtt (51Q-htt). Some of them inhibited its aggregation in vitro by stabilizing the monomer. They also recognized 103Q-htt but not 20Q-htt (nonpathogenic length). Inhibition of aggregation corresponded with reduced leakage of a fluorescent probe from liposomes and diminished oxidative stress in RBCs. The presence of aptamers was able to rescue the sequestration of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by aggregated mhtt. Some of the aptamers were able to enhance the partitioning of mhtt in the soluble fraction in a yeast model of HD. They were also able to rescue endocytotic defect due to aggregation of mhtt. The beneficial effect of a combination of aptamers was enhanced with improvement in cell survival. Since HD is a monogenic autosomal dominant disorder, aptamers may be developed as a viable strategy to slow down the progress of the disease. Since they are nonimmunogenic and nontoxic, aptamers may emerge as strong candidates to reduce protein-protein interaction and hence protein aggregation in protein misfolding disorders in general.
authors: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India.
authors: Rajeev K
authors: RK
authors: Chaudhary
authors: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India.
authors: Kinjal A
authors: KA
authors: Patel
authors: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India.
authors: Milan K
authors: MK
authors: Patel
authors: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India.
authors: Radha H
authors: RH
authors: Joshi
authors: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India.
authors: Ipsita
authors: I
authors: Roy
mesh_terms: D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000737:chemistry / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D009690:Nucleic Acid Conformation; D009696:Nucleic Acids / Q000737:chemistry; D018384:Oxidative Stress; D010455:Peptides / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D017423:Sequence Analysis, RNA
chemical_list: D052157:Aptamers, Nucleotide; C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009696:Nucleic Acids; D010455:Peptides; C097188:polyglutamine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases