title: Self-assembly and sequence length dependence on nanofibrils of polyglutamine peptides.
abstract: Huntington's disease (HD) is recognized as a currently incurable, inherited neurodegenerative disorder caused by the accumulation of misfolded polyglutamine (polyQ) peptide aggregates in neuronal cells. Yet, the mechanism by which newly formed polyQ chains interact and assemble into toxic oligomeric structures remains a critical, unresolved issue. In order to shed further light on the matter, our group elected to investigate the folding of polyQ peptides - examining glutamine repeat lengths ranging from 3 to 44 residues. To characterize these aggregates we employed a diverse array of technologies, including: nuclear magnetic resonance; circular dichroism; Fourier transform infrared spectroscopy; fluorescence resonance energy transfer (FRET), and atomic force microscopy. The data we obtained suggest that an increase in the number of glutamine repeats above 14 residues results in disordered loop structures, with different repeat lengths demonstrating unique folding characteristics. This differential folding manifests in the formation of distinct nano-sized fibrils, and on this basis, we postulate the idea of 14 polyQ repeats representing a critical loop length for neurotoxicity - a property that we hope may prove amenable to future therapeutic intervention. Furthermore, FRET measurements on aged assemblages indicate an increase in the end-to-end distance of the peptide with time, most probably due to the intermixing of individual peptide strands within the nanofibril. Further insight into this apparent time-dependent reorganization of aggregated polyQ peptides may influence future disease modeling of polyQ-related proteinopathies, in addition to directing novel clinical innovations.
authors.affiliation: Biomaterials & Advanced Drug Delivery Laboratory (BioADD), Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA; Bioorganic and Neurochemistry Laboratory, Central Leather Research Institute, Adyar, Chennai, Tamilnadu, India; Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Inayathullah
authors.affiliation: Biomaterials & Advanced Drug Delivery Laboratory (BioADD), Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA; UCL Medical School, University College London (UCL), London, UK; University College London Hospitals NHS Foundation Trust, London, UK. Electronic address: aaron.tan@ucl.ac.uk.
authors.forename: Aaron
authors.initials: A
authors.lastname: Tan
authors.affiliation: UCL Medical School, University College London (UCL), London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jeyaraj
authors.affiliation: UCL Medical School, University College London (UCL), London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Lam
authors.affiliation: Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA; School of Materials Science and Engineering, Nanyang Technological University, Singapore.
authors.forename: Nam-Joon
authors.initials: NJ
authors.lastname: Cho
authors.affiliation: Stanford Magnetic Resonance Laboratory, Stanford University, Palo Alto, CA, USA.
authors.forename: Corey W
authors.initials: CW
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA.
authors.forename: Martin A C
authors.initials: MA
authors.lastname: Manoukian
authors.affiliation: Department of Neurosurgery, King's College Hospital NHS Foundation Trust, King's College London, London, UK.
authors.forename: Keyoumars
authors.initials: K
authors.lastname: Ashkan
authors.affiliation: Biomaterials & Advanced Drug Delivery Laboratory (BioADD), Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA; Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA.
authors.forename: Morteza
authors.initials: M
authors.lastname: Mahmoudi
authors.affiliation: Biomaterials & Advanced Drug Delivery Laboratory (BioADD), Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA; Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA. Electronic address: jayraja@stanford.edu.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
mesh_terms: D000818:Animals; D031541:Fluorescence Resonance Energy Transfer; D005973:Glutamine / Q000737:chemistry; D006801:Humans; D000071058:Huntingtin Protein / Q000737:chemistry*; D006816:Huntington Disease / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D017510:Protein Folding; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000071058:Huntingtin Protein; D010455:Peptides; D005973:Glutamine; C097188:polyglutamine
keywords: Huntington's disease; Misfolded polyglutamine; Nanofibrils; Neurodegenerative disease; PolyQ peptides; Polyglutamine disease