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RAS–MAPK–MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1

Abstract

Many neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein’s resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS–MAPK–MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases.

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Figure 1: Integrative genetic screen identifies regulators of ATXN1(82Q) stability.
Figure 2: Modifiers shared between cell-based and in vivo screens.
Figure 3: Upstream MAPK pathway components regulate ATXN1 toxicity and levels.
Figure 4: MSK1 phosphorylates ATXN1 at S776 and controls its stability.
Figure 5: Pharmacological inhibition of the MAPK pathway decreases ATXN1 level.
Figure 6: Msk reduction rescues behavioural and pathological phenotypes in SCA1 mice.

References

  1. Evans, D. A. Estimated prevalence of Alzheimer’s disease in the United States. Milbank Q. 68, 267–289 (1990)

    CAS  Article  Google Scholar 

  2. Hindle, J. V. Ageing, neurodegeneration and Parkinson’s disease. Age Ageing 39, 156–161 (2010)

    Article  Google Scholar 

  3. Marsden, C. D. & Parkes, J. D. Success and problems of long-term levodopa therapy in Parkinson’s disease. Lancet 1, 345–349 (1977)

    CAS  Article  Google Scholar 

  4. Scarpini, E., Scheltens, P. & Feldman, H. Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol. 2, 539–547 (2003)

    CAS  Article  Google Scholar 

  5. Ross, C. A. & Poirier, M. A. Protein aggregation and neurodegenerative disease. Nature Med. 10, S10–S17 (2004)

    Article  Google Scholar 

  6. Taylor, J. P., Hardy, J. & Fischbeck, K. H. Toxic proteins in neurodegenerative disease. Science 296, 1991–1995 (2002)

    CAS  Article  ADS  Google Scholar 

  7. Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007)

    CAS  Article  Google Scholar 

  8. Zoghbi, H. Y. & Orr, H. T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247 (2000)

    CAS  Article  Google Scholar 

  9. Singleton, A. B. et al. α-synuclein locus triplication causes Parkinson’s disease. Science 302, 841 (2003)

    CAS  Article  Google Scholar 

  10. Chartier-Harlin, M. C. et al. α-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167–1169 (2004)

    CAS  Article  Google Scholar 

  11. Rovelet-Lecrux, A. et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature Genet. 38, 24–26 (2006)

    CAS  Article  Google Scholar 

  12. Götz, J. & Ittner, L. M. Animal models of Alzheimer’s disease and frontotemporal dementia. Nature Rev. Neurosci. 9, 532–544 (2008)

    Article  Google Scholar 

  13. Williams, A. J. & Paulson, H. L. Polyglutamine neurodegeneration: protein misfolding revisited. Trends Neurosci. 31, 521–528 (2008)

    CAS  Article  Google Scholar 

  14. Xia, H. et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nature Med. 10, 816–820 (2004)

    CAS  Article  Google Scholar 

  15. Harper, S. Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc. Natl Acad. Sci. USA 102, 5820–5825 (2005)

    CAS  Article  ADS  Google Scholar 

  16. Yamamoto, A., Lucas, J. J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101, 57–66 (2000)

    CAS  Article  Google Scholar 

  17. Zu, T. et al. Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice. J. Neurosci. 24, 8853–8861 (2004)

    CAS  Article  Google Scholar 

  18. Kordasiewicz, H. B. et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74, 1031–1044 (2012)

    CAS  Article  Google Scholar 

  19. Zoghbi, H. Y. & Orr, H. T. Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1. J. Biol. Chem. 284, 7425–7429 (2009)

    CAS  Article  Google Scholar 

  20. Emamian, E. S. et al. Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38, 375–387 (2003)

    CAS  Article  Google Scholar 

  21. Noble, M. E., Endicott, J. A. & Johnson, L. N. Protein kinase inhibitors: insights into drug design from structure. Science 303, 1800–1805 (2004)

    CAS  Article  ADS  Google Scholar 

  22. Fernandez-Funez, P. et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–106 (2000)

    CAS  Article  ADS  Google Scholar 

  23. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critial nodes in signalling pathways: insights into insulin action. Nature Rev. Mol. Cell Biol. 7, 85–96 (2006)

    CAS  Article  Google Scholar 

  24. Shaharabany, M. et al. Distinct pathways for the involvement of WNK4 in the signaling of hypertonicity and EGF. FEBS J. 275, 1631–1642 (2008)

    CAS  Article  Google Scholar 

  25. Teixeira-Castro, A. et al. Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways. Hum. Mol. Genet. 20, 2996–3009 (2011)

    CAS  Article  Google Scholar 

  26. Cobb, M. H. MAP kinase pathways. Prog. Biophys. Mol. Biol. 71, 479–500 (1999)

    CAS  Article  Google Scholar 

  27. Avruch, J. Insulin signal transduction through protein kinase cascades. Mol. Cell. Biochem. 182, 31–48 (1998)

    CAS  Article  Google Scholar 

  28. Al-Ramahi, I. et al. dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. PLoS Genet. 3, e234 (2007)

    Article  Google Scholar 

  29. Jorgensen, N. D. et al. Phosphorylation of ATXN1 at Ser776 in the cerebellum. J. Neurochem. 110, 675–686 (2009)

    CAS  Article  Google Scholar 

  30. Roux, P. P. & Blenis, J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 68, 320–344 (2004)

    CAS  Article  Google Scholar 

  31. Mody, N., Leitch, J., Armstrong, C., Dixon, J. & Cohen, P. Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway. FEBS Lett. 502, 21–24 (2001)

    CAS  Article  Google Scholar 

  32. Lackey, K. et al. The discovery of potent cRaf1 kinase inhibitors. Bioorg. Med. Chem. Lett. 10, 223–226 (2000)

    CAS  Article  Google Scholar 

  33. Deak, M., Clifton, A. D., Lucocq, L. M. & Alessi, D. R. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 17, 4426–4441 (1998)

    CAS  Article  Google Scholar 

  34. Lorenzetti, D. et al. Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus. Hum. Mol. Genet. 9, 779–785 (2000)

    CAS  Article  Google Scholar 

  35. Watase, K. et al. A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34, 905–919 (2002)

    CAS  Article  Google Scholar 

  36. Arthur, J. S. & Cohen, P. MSK1 is required for CREB phosphorylation in response to mitogens in mouse embryonic stem cells. FEBS Lett. 482, 44–48 (2000)

    CAS  Article  Google Scholar 

  37. Wiggin, G. R. et al. MSK1 and MSK2 are required for the mitogen- and stress- induced phosphorylation of CREB and ATF1 in fibroblasts. Mol. Cell. Biol. 22, 2871–2881 (2002)

    CAS  Article  Google Scholar 

  38. Burright, E. N. et al. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82, 937–948 (1995)

    CAS  Article  Google Scholar 

  39. Dar, A. C., Das, T. K., Shokat, K. M. & Cagan, R. L. Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486, 80–84 (2012)

    CAS  Article  ADS  Google Scholar 

  40. van Ham, T. J., Breitling, R., Swertz, M. A. & Nollen, E. A. Neurodegenerative diseases: lessons from genome-wide screens in small model organisms. EMBO Mol. Med. 1, 360–370 (2009)

    CAS  Article  Google Scholar 

  41. Jeong, H. et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137, 60–72 (2009)

    CAS  Article  Google Scholar 

  42. Matsumoto, M. et al. Molecular clearance of ataxin-3 is regulated by a mammalian E4. EMBO J. 23, 659–669 (2004)

    CAS  Article  Google Scholar 

  43. Cummings, C. J. et al. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24, 879–892 (1999)

    CAS  Article  Google Scholar 

  44. Chin, L. & Gray, J. W. Translating insights from the cancer genome into clinical practice. Nature 452, 553–563 (2008)

    CAS  Article  ADS  Google Scholar 

  45. Falsig, J. & Aguzzi, A. The prion organotypic slice culture assay—POSCA. Nature Protocols 3, 555–562 (2008)

    CAS  Article  Google Scholar 

  46. Jafar-Nejad, P., Ward, C. S., Richman, R., Orr, H. T. & Zoghbi, H. Y. Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14–3-3 haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration. Proc. Natl Acad. Sci. USA 108, 2142–2147 (2011)

    CAS  Article  ADS  Google Scholar 

  47. Bowman, A. B. et al. Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nature Genet. 39, 373–379 (2007)

    CAS  Article  Google Scholar 

  48. Lim, J. et al. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452, 713–718 (2008)

    CAS  Article  ADS  Google Scholar 

  49. Servadio, A. et al. Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nature Genet. 10, 94–98 (1995)

    CAS  Article  Google Scholar 

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Acknowledgements

We thank the members of the Zoghbi, Botas, Orr and Westbrook laboratories for suggestions and discussions, and V. Brandt for editorial input. We also appreciate the help from CCSC and C-BASS cores at The Baylor College of Medicine (BCM) for FACS analysis and the confocal microscopy and mouse behavioural cores of the BCM Intellectual and Developmental Disabilities Research Center (HD024064). Thanks to J. Barrish at Texas Children’s Hospital for help with scanning electron microscopy. This work was supported by a Howard Hughes Medical Institute Collaborative Innovation Awards grant and grant NIH-NS42179 (J.B.) I.A.-R. was supported by an NIH Brain Disorders and Development training grant.

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J.P., I.A.-R., Q.T., N.M., H.T.O., T.F.W., J.B. and H.Y.Z. designed the experiments. J.P., I.A.-R., Q.T., N.M., J.R.D.-G., T.G.-F., H.-C.L., S.L., L.D., H.K., Y.L., P.J.-N., L.S.S., R.R., X.L. and Y.G. performed the research. J.P., I.A.-R., Q.T., N.M., J.R.D.-G., T.G.-F., H.-C.L., S.L., L.D., H.K., Y.L., P.J.-N., C.A.S., J.S.C.A., H.T.O., T.F.W., J.B. and H.Y.Z. analysed and interpreted the data. J.P., I.A.-R., H.T.O., T.F.W., J.B. and H.Y.Z. wrote and edited the paper.

Corresponding authors

Correspondence to Harry T. Orr, Thomas F. Westbrook, Juan Botas or Huda Y. Zoghbi.

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The authors declare no competing financial interests.

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This file contains the N number for Figure 6c in the main paper, Supplementary Figures 1-8, Supplementary Tables 1-4, the genotypes for Drosophila and additional references. (PDF 2136 kb)

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Park, J., Al-Ramahi, I., Tan, Q. et al. RAS–MAPK–MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 498, 325–331 (2013). https://doi.org/10.1038/nature12204

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