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Molecular Neurodegeneration

Open Access

Phosphorylation of hnRNP K controls cytosolic accumulation of TDP-43

  • Anthony White1,
  • Diane Moujalled1,
  • Janine James1,
  • Alexandra Grubman1,
  • Katja Kanninen2 and
  • Peter Crouch1
Molecular Neurodegeneration20138(Suppl 1):P46

Published: 13 September 2013


ParaquatMotor Neuron DiseaseFrontotemporal DementiaStress GranuleSodium Arsenite


TAR-DNA binding protein 43 (TDP-43) is a heterogeneous ribonucleoprotein (hnRNP) identified as a major protein constituent of cytosolic inclusions in spinal cord of patients with motor neuron disease. The inclusions are formed by movement of TDP-43 from its predominantly nuclear localization to the cytosol, followed by accumulation of ubiquitinated and phosphorylated C-terminal TDP-43 fragments. The mechanisms controlling TDP-43 trafficking and accumulation are not well known, however, it has been demonstrated previously that kinases control movement and accumulation of hnRNPs. Therefore, we investigated whether kinases also controlled TDP-43 accumulation during cell stress.

Materials and methods

Neuronal cultures were treated with the mitochondrial inhibitors paraquat or sodium arsenite, or transfected with C-terminal TDP-43 or full length TDP-43 constructs and examined for kinase control of TDP-43 localization.


We found that stress induction induced robust cytosolic accumulation of C-terminal TDP-43 into RNA stress granules, some of which progress to ubiquitinated inclusions. Inhibitors of c-Jun N-terminal kinase (JNK) and cyclin-dependent kinase 2 (CDK2) specifically inhibit and/or reverse the cytosolic accumulation of TDP-43 with little effect on ubiquitous stress granule formation. Our studies have shown active CDK2 co-localizes with accumulated TDP-43 and heterogeneous ribonucleoprotein K (hnRNP K). CDK2 inhibition blocks phosphorylation of hnRNP K, preventing its incorporation into stress granules. Due to Interaction between hnRNP K with TDP-43, the loss of hnRNP K from stress granules prevents accumulation of TDP-43. We have also determined that specific C-terminal mutations to TDP-43 alter expression of hnRNP K during cell stress. Preliminary studies indicate that this may involve altered hnRNP K phosphorylation.


Due to the recently identified role for hnRNPs in motor neuron disease and frontotemporal dementia, further investigation of the association between hnRNP K and TDP-43 is warranted. Understanding how kinase activity modulates TDP-43 accumulation may provide new pharmacological targets for disease intervention.



This research was supported by funds from the Motor Neuron Disease Research Institute of Australia.

Authors’ Affiliations

Department of Pathology, The University of Melbourne, Parkville, Australia
Laboratory of Molecular Brain Research, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland


© White et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.