Abstract
Motor neuron disease (MND) is a progressive neurodegenerative disease with no effective treatment. One of the principal pathological hallmarks is the deposition of TAR DNA binding protein 43 (TDP-43) in cytoplasmic inclusions. TDP-43 aggregation occurs in both familial and sporadic MND; however, the mechanism of endogenous TDP-43 aggregation in disease is incompletely understood. This study focused on the induction of cytoplasmic accumulation of endogenous TDP-43 in the motor neuronal cell line NSC-34. The endoplasmic reticulum (ER) stressor tunicamycin induced casein kinase 1 (CK1)-dependent cytoplasmic accumulation of endogenous TDP-43 in differentiated NSC-34 cells, as seen by immunocytochemistry. Immunoblotting showed that induction of ER stress had no effect on abundance of TDP-43 or phosphorylated TDP-43 in the NP-40/RIPA soluble fraction. However, there were significant increases in abundance of TDP-43 and phosphorylated TDP-43 in the NP-40/RIPA-insoluble, urea-soluble fraction, including high molecular weight species. In all cases, these increases were lowered by CK1 inhibition. Thus ER stress signalling, as induced by tunicamycin, causes CK1-dependent phosphorylation of TDP-43 and its consequent cytosolic accumulation.
Highlights
Motor neuron disease (MND, known as amyotrophic lateral sclerosis) is a progressive, incurable and fatal neurodegenerative disease [1]
The tunicamycin-induced TAR DNA binding protein 43 (TDP-43) inclusions are large in size, often with a single large inclusion per cell (Fig. 1), and resemble the rounded TDP-43 inclusions found in the motor cortex of people with MND [57]
We show that stress treatments of cultured NSC-34 cells induced different patterns of TDP-43 and TIAR/ G3BP1-positive inclusions, supporting the hypothesis that in sporadic MND, TDP-43 aggregation is potentiated by cellular stress
Summary
Motor neuron disease (MND, known as amyotrophic lateral sclerosis) is a progressive, incurable and fatal neurodegenerative disease [1]. TDP-43 aggregation, which can be caused by mutations in a minority of cases, has been demonstrated to interfere with nucleocytoplasmic transport and compounds capable of blocking TDP43 aggregation in C. elegans have been discovered which improve viability [11,12,13,14,15,16]. It is not yet clear whether the TDP-43 aggregates result in toxicity via loss of function of the nuclear protein, or whether the aggregates confer a toxic gain of function [17,18,19]
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