Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss

  • A Corrigendum to this article was published on 25 November 2015

Abstract

The defining pathogenic feature of Parkinson's disease is the age-dependent loss of dopaminergic neurons. Mutations and inactivation of parkin, an ubiquitin E3 ligase, induce Parkinson's disease through accumulation of pathogenic substrates. We found that transgenic overexpression of a parkin substrate, aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2), led to a selective, age-dependent, progressive loss of dopaminergic neurons via activation of poly(ADP-ribose) polymerase-1 (PARP1). AIMP2 accumulation in vitro and in vivo resulted in PARP1 overactivation and dopaminergic cell toxicity via direct association of these proteins in the nucleus, providing a path to PARP1 activation other than DNA damage. Inhibition of PARP1 through gene deletion or drug inhibition reversed behavioral deficits and protected against dopamine neuron death in AIMP2 transgenic mice. These data indicate that brain-permeable PARP inhibitors could effectively delay or prevent disease progression in Parkinson's disease.

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Figure 1: Generation and characterization of conditional AIMP2 transgenic mice.
Figure 2: AIMP2 accumulation leads to a progressive and selective degeneration of dopaminergic neurons in the substantia nigra of transgenic mice.
Figure 3: Progressive motor deficit and reduction of dopamine and dopaminergic fiber densities in the striatum of AIMP2 transgenic mice.
Figure 4: AIMP2 accumulation leads to PARP1 activation and cell death.
Figure 5: AIMP2-induced degeneration of dopamine neurons is rescued by genetic deletion of PARP1.
Figure 6: PARP inhibition protects against AIMP2-induced dopaminergic toxicity.

Change history

  • 01 June 2015

    In the version of this article initially published, the image in Figure 2c described as being from 20-month-old transgenic mice was actually from 2-month-old control mice. New representative images showing a wider field of view have been provided for all of Figure 2c, and Figure 2d has been replaced by a new quantification performed independently of the original one. This quantification (n = 3) yielded a P value for the comparison between the 2-month-old control and transgenic of <0.001, as compared to <0.01 in the original. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (NS38377) and the JPB Foundation. Y.-I.L. was supported by the Samsung Scholarship Foundation. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors acknowledge the joint participation and support by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with the Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation's Parkinson's Disease Programs. D.S. and L.T. were supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, US National Institutes of Health.

Author information

Y.L. designed and performed the in vitro and in vivo experiments. S.S.K. performed the HPLC analysis and behavior tests. J.-H.S. and Y.-I.L. performed stereotaxic intranigral virus injection and stereological counting of tyrosine hydroxylase–positive neurons. Y.-I.L. performed subcellular fractionation and confocal microscopy. H.S.K., B.D.L., H.C.K., S.-U.K. and D.K. provided materials and helped with the analysis of the results. H.J. performed immunofluorescence and cell counting for the intracortical virus injection samples. D.S. and L.T. performed pronuclear injections of the TetP-AIMP2 construct and provided founder mice. V.L.D. and T.M.D. formulated the hypothesis, initiated and organized the study and wrote the manuscript. Y.L., V.L.D. and T.M.D. contributed to the final manuscript.

Correspondence to Valina L Dawson or Ted M Dawson.

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Lee, Y., Karuppagounder, S., Shin, J. et al. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat Neurosci 16, 1392–1400 (2013). https://doi.org/10.1038/nn.3500

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