Biochemistry and Pharmacology - Research Publications

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Author: Ang, Ching-Seng × Author: Hatters, Daniel × Author: Haynes, Angelique × Author: Reid, Gavin × Type: Journal Article ×

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    Arginine in C9ORF72 Dipolypeptides Mediates Promiscuous Proteome Binding and Multiple Modes of Toxicity
    Radwan, M ; Ang, C-S ; Ormsby, AR ; Cox, D ; Daly, JC ; Reid, GE ; Hatters, DM (ELSEVIER, 2020-04)
    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 synthesis. Poly-GR also recruited arginine methylases, induced hypomethylation of endogenous proteins, and induced a profound destabilization of the actin cytoskeleton. Our findings point to arginine in GR and PR polymers as multivalent toxins to translation as well as arginine methylation that may explain the dysfunction of biological processes including ribosome biogenesis, mRNA splicing and cytoskeleton assembly.
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    Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis
    Ramdzan, YM ; Trubetskov, MM ; Ormsby, AR ; Newcombe, EA ; Sui, X ; Tobin, MJ ; Bongiovanni, MN ; Gras, SL ; Dewson, G ; Miller, JML ; Finkbeiner, S ; Moily, NS ; Niclis, J ; Parish, CL ; Purcell, AW ; Baker, MJ ; Wilce, JA ; Waris, S ; Stojanovski, D ; Bocking, T ; Ang, C-S ; Ascher, DB ; Reid, GE ; Hatters, DM (CELL PRESS, 2017-05-02)
    Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1) inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion domain-containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species, and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where sequestration of soluble Httex1 inclusions can remove the trigger for apoptosis but also co-aggregate other proteins, which curtails cellular metabolism and leads to a slow death by necrosis.