Arginine in C9ORF72 Dipolypeptides Mediates Promiscuous Proteome Binding and Multiple Modes of Toxicity
Mona Radwan, Ching-Seng Ang, Angelique R Ormsby, Dezerae Cox, James C Daly, Gavin E Reid, Danny M Hatters
MOLECULAR & CELLULAR PROTEOMICS | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Published : 2020
C9ORF72-associated Motor Neuron Disease patients feature abnormal expression of 5 dipeptide repeat (DPR) polymers. Here we used quantitative proteomics in a mouse neuronal-like cell line (Neuro2a) to demonstrate that the Arg residues in the most toxic DPRS, PR and GR, leads to a promiscuous binding to the proteome compared with a relative sparse binding of the more inert AP and GA. Notable targets included ribosomal proteins, translation initiation factors and translation elongation factors. PR and GR comprising more than 10 repeats appeared to robustly stall on ribosomes during translation suggesting Arg-rich peptide domains can electrostatically jam the ribosome exit tunnel during synthesi..View full abstract
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Awarded by National Health and Medical Research Council
Awarded by Australian Research Council
This work was funded by grants to DMH (National Health and Medical Research Council APP1161803 and Motor Neuron Disease Research Institute, Australia small grant) and to DMH and GER (Australian Research Council DP170103093). MR acknowledges support from an Australian Government Research Training Program (RTP) Scholarship and an Egyptian Ministry of Higher Education and Scientific Research PhD scholarship.