title: The Glycine-Alanine Dipeptide Repeat from C9orf72 Hexanucleotide Expansions Forms Toxic Amyloids Possessing Cell-to-Cell Transmission Properties.
abstract: Hexanucleotide expansions, GGGGCC, in the non-coding regions of the C9orf72 gene were found in major frontotemporal lobar dementia and amyotrophic lateral sclerosis patients (C9FTD/ALS). In addition to possible RNA toxicity, several dipeptide repeats (DPRs) are translated through repeat-associated non-ATG-initiated translation. The DPRs, including poly(GA), poly(GR), poly(GP), poly(PR), and poly(PA), were found in the brains and spinal cords of C9FTD/ALS patients. Among the DPRs, poly(GA) is highly susceptible to form cytoplasmic inclusions, which is a characteristic of C9FTD/ALS. To elucidate DPR aggregation, we used synthetic (GA)15 DPR as a model system to examine the aggregation and structural properties in vitro. We found that (GA)15 with 15 repeats fibrillates rapidly and ultimately forms flat, ribbon-type fibrils evidenced by transmission electron microscopy and atomic force microscopy. The fibrils are capable of amyloid dye binding and contain a characteristic cross-β sheet structure, as revealed by x-ray scattering. Furthermore, using neuroblastoma cells, we demonstrated the neurotoxicity and cell-to-cell transmission property of (GA)15 DPR. Overall, our results show the structural and toxicity properties of GA DPR to facilitate future DPR-related therapeutic development.
authors.affiliation: From the Genomics Research Center and.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: the National Synchrotron Radiation Research Center, 101 Hsin-Ann Road, Science Park, Hsinchu 30076, Taiwan, and the Chemical Engineering Department and.
authors.forename: U-Ser
authors.initials: US
authors.lastname: Jeng
authors.affiliation: Institute of Physics, Academia Sinica, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan, Department of Material Science and Engineering, National Tsing-Hua University, Hsinchu 30013, Taiwan.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chiang
authors.affiliation: Institute of Physics, Academia Sinica, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan, Department of Material Science and Engineering, National Tsing-Hua University, Hsinchu 30013, Taiwan.
authors.forename: Ing-Shouh
authors.initials: IS
authors.lastname: Hwang
authors.affiliation: From the Genomics Research Center and yrchen@gate.sinica.edu.tw.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
mesh_terms: D000409:Alanine; D000682:Amyloid / Q000737:chemistry* / Q000633:toxicity; D000073885:C9orf72 Protein; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D005998:Glycine; D006801:Humans; D009474:Neurons / Q000187:drug effects; D011506:Proteins / Q000737:chemistry* / Q000633:toxicity; D019680:Trinucleotide Repeat Expansion
chemical_list: D000682:Amyloid; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D011506:Proteins; D000409:Alanine; D005998:Glycine
keywords: C9orf72; GA; aggregation; amyloid; amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); dipeptide repeat; fibril; toxicity