Poly(ADP-ribosylation) regulates key features of motor neuron disease

Abstract

In >95% of motor neuron disease (MND) the normally nuclear protein TDP-43 exits the nucleus and accumulates as hyperphosphorylated cytoplasmic aggregates in affected neurons and glia. Insight into the cellular mechanisms that trigger the nuclear clearance and subsequent phosphorylation of TDP-43 may provide a platform for the development of novel therapeutic strategies. Today I will demonstrate that poly(ADP-ribosylation), a reversible protein modification, regulates disease-associated toxicity, subcellular localization and hyperphosphorylation of TDP-43. These findings implicate poly(ADP-ribosylation) activity as a potential therapeutic target in MND and pave the way for future studies into the broader role of poly(ADP-ribosylation) in the nervous system.