Abstract:
Hexanucleotide G4C2 repeat expansion in the non-coding regions of the C9ORF72 (C9) gene is the most prevalent mutation among the patients carrying frontotemporal lobar dementia (FTD) and amyotrophic lateral sclerosis (ALS). The patients carry over ~30 to hundreds/thousands of repeats translated to dipeptide repeats (DPRs), including poly(GA), poly(GR), poly(GP), poly(PR), and poly(PA). The inclusions of DPRs could be found in brain and spinal cord of C9FTD/ALS patients. We first worked on poly(GA) that highly susceptible to form cytoplasmic inclusions among the DPRs. By several biophysical assays including wide angle x-ray scattering (WAXS) in collaboration with Dr. U-Ser Jeng’s team, we found synthetic poly(GA) with 15 repeats forms flat, ribbon-type fibrils with a characteristic cross-β sheet structure. We also demonstrated the neurotoxicity and cell-to-cell transmission property. Furthermore, we investigated the most toxic forms of DPRs, that are poly-glycine-arginine (GR) and poly-proline-arginine (PR). Currently, the structure-function relationship is still unknown. By using small angle x-ray scattering (SAXS), we found extension of the repeat number led to a helical structure disrupting plasma and nuclear membrane. We will discuss the toxicity mechanism and the potential therapeutic development.
Keywords - dipeptide repeats, neurodegenerative diseases, WAXS/SAXS, fibrils, membranes
References:
- Yu-Jen Chang, U-Ser Jeng, Ya-Ling Chiang, Ing-Shouh Hwang, and Yun-Ru Chen*. The Glycine-Alanine Dipeptide Repeat from C9orf72 Hexanucleotide Expansions Forms Toxic Amyloids Possessing Cell-to-cell Transmission Properties. J Biol. Chem., 291(10):4903-11. (2016)