title: Assessing a peptidylic inhibitor-based therapeutic approach that simultaneously suppresses polyglutamine RNA- and protein-mediated toxicities in patient cells and Drosophila.
abstract: Polyglutamine (polyQ) diseases represent a group of progressive neurodegenerative disorders that are caused by abnormal expansion of CAG triplet nucleotides in disease genes. Recent evidence indicates that not only mutant polyQ proteins, but also their corresponding mutant RNAs, contribute to the pathogenesis of polyQ diseases. Here, we describe the identification of a 13-amino-acid peptide, P3, which binds directly and preferentially to long-CAG RNA within the pathogenic range. When administered to cell and Drosophila disease models, as well as to patient-derived fibroblasts, P3 inhibited expanded-CAG-RNA-induced nucleolar stress and suppressed neurotoxicity. We further examined the combined therapeutic effect of P3 and polyQ-binding peptide 1 (QBP1), a well-characterized polyQ protein toxicity inhibitor, on neurodegeneration. When P3 and QBP1 were co-administered to disease models, both RNA and protein toxicities were effectively mitigated, resulting in a notable improvement of neurotoxicity suppression compared with the P3 and QBP1 single-treatment controls. Our findings indicate that targeting toxic RNAs and/or simultaneous targeting of toxic RNAs and their corresponding proteins could open up a new therapeutic strategy for treating polyQ degeneration.
authors.affiliation: Laboratory of Drosophila Research, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Biochemistry Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Laboratory of Drosophila Research, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Biochemistry Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Ho
authors.initials: H
authors.lastname: Tsoi
authors.affiliation: Laboratory of Drosophila Research, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Biochemistry Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Program of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Pan P
authors.initials: PP
authors.lastname: Li
authors.affiliation: Biochemistry Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Cell and Molecular Biology Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Molecular Biotechnology Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Kwok-Fai
authors.initials: KF
authors.lastname: Lau
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Program of Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Dobrila D
authors.initials: DD
authors.lastname: Rudnicki
authors.affiliation: Biochemistry Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Cell and Molecular Biology Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Jacky Chi-Ki
authors.initials: JC
authors.lastname: Ngo
authors.affiliation: Laboratory of Drosophila Research, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Biochemistry Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Cell and Molecular Biology Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China Molecular Biotechnology Program, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China hyechan@cuhk.edu.hk.
authors.forename: Ho Yin Edwin
authors.initials: HY
authors.lastname: Chan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004331:Drosophila melanogaster / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D009410:Nerve Degeneration / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010750:Phosphoproteins / Q000378:metabolism; D012313:RNA / Q000633:toxicity*; D012335:RNA, Ribosomal / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D013312:Stress, Physiological; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D000097796:Nucleolin
chemical_list: D010455:Peptides; D010750:Phosphoproteins; D012313:RNA; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C097188:polyglutamine
keywords: Expanded-CAG RNA; Expanded-polyQ protein; Nucleolin; P3; Polyglutamine disease; QBP1; Spinocerebellar ataxia
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