Progressive degeneration of human neural stem cells caused by pathogenic LRRK2 (original) (raw)

References

1. Liu, G. H. et al. Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome. Nature 472, 221–225 (2011)
   Article ADS CAS Google Scholar
2. Dechat, T. et al. Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev. 22, 832–853 (2008)
   Article CAS Google Scholar
3. Kudlow, B. A., Kennedy, B. K. & Monnat, R. J., Jr Werner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nature Rev. Mol. Cell Biol. 8, 394–404 (2007)
   Article CAS Google Scholar
4. Worman, H. J., Ostlund, C. & Wang, Y. Diseases of the nuclear envelope. Cold Spring Harb. Perspect. Biol. 2, a000760 (2010)
   Article Google Scholar
5. Winner, B. et al. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol. Dis. 41, 706–716 (2011)
   Article CAS Google Scholar
6. Chang, K. H. et al. Nuclear envelope dispersion triggered by deregulated Cdk5 precedes neuronal death. Mol. Biol. Cell 22, 1452–1462 (2011)
   Article Google Scholar
7. Tran, D., Chalhoub, A., Schooley, A., Zhang, W. & Ngsee, J. K. A mutation in VAPB that causes amyotrophic lateral sclerosis also causes a nuclear envelope defect. J. Cell Sci. 125, 2831–2836 (2012)
   Article CAS Google Scholar
8. Padiath, Q. S. et al. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nature Genet. 38, 1114–1123 (2006)
   Article CAS Google Scholar
9. Woulfe, J. M. Abnormalities of the nucleus and nuclear inclusions in neurodegenerative disease: a work in progress. Neuropathol. Appl. Neurobiol. 33, 2–42 (2007)
   CAS PubMed Google Scholar
10. Cookson, M. R. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nature Rev. Neurosci. 11, 791–797 (2010)
    Article CAS Google Scholar
11. Cookson, M. R. & Bandmann, O. Parkinson's disease: insights from pathways. Hum. Mol. Genet. 19, R21–R27 (2010)
    Article CAS Google Scholar
12. Deng, X. et al. Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nature Chem. Biol. 7, 203–205 (2011)
    Article CAS Google Scholar
13. Lee, B. D. et al. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nature Med. 16, 998–1000 (2010)
    Article CAS Google Scholar
14. Li, W. et al. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors. Proc. Natl Acad. Sci. USA 108, 8299–8304 (2011)
    Article ADS CAS Google Scholar
15. Krishnan, V. et al. Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc. Natl Acad. Sci. USA 108, 12325–12330 (2011)
    Article ADS CAS Google Scholar
16. Cheung, I. et al. Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proc. Natl Acad. Sci. USA 107, 8824–8829 (2010)
    Article ADS CAS Google Scholar
17. Xie, W. et al. Proteasome inhibition modeling nigral neuron degeneration in Parkinson's disease. J. Neurochem. 115, 188–199 (2010)
    Article CAS Google Scholar
18. Liu, G. H. et al. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell 8, 688–694 (2011)
    Article CAS Google Scholar
19. Suzuki, K. et al. Highly efficient transient gene expression and gene targeting in primate embryonic stem cells with helper-dependent adenoviral vectors. Proc. Natl Acad. Sci. USA 105, 13781–13786 (2008)
    Article ADS CAS Google Scholar
20. Li, M. et al. Efficient correction of hemoglobinopathy-causing mutations by homologous recombination in integration-free patient iPSCs. Cell Res. 21, 1740–1744 (2011)
    Article ADS CAS Google Scholar
21. Aizawa, E. et al. Efficient and accurate homologous recombination in hESCs and hiPSCs using helper-dependent adenoviral vectors. Mol. Ther. 20, 424–431 (2012)
    Article CAS Google Scholar
22. Rudenko, I. N., Chia, R. & Cookson, M. R. Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease? BMC Med. 10, 20 (2012)
    Article CAS Google Scholar
23. Kanao, T. et al. Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila . Hum. Mol. Genet. 19, 3747–3758 (2010)
    Article CAS Google Scholar
24. Gehrke, S., Imai, Y., Sokol, N. & Lu, B. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466, 637–641 (2010)
    Article ADS CAS Google Scholar
25. Nichols, R. J. et al. 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochem. J. 430, 393–404 (2010)
    Article CAS Google Scholar
26. Dzamko, N. et al. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14–3-3 binding and altered cytoplasmic localization. Biochem. J. 430, 405–413 (2010)
    Article CAS Google Scholar
27. Scaffidi, P. & Misteli, T. Lamin A-dependent nuclear defects in human aging. Science 312, 1059–1063 (2006)
    Article ADS CAS Google Scholar
28. Poulopoulos, M. et al. Clinical and Pathological Characteristics of LRRK2 G2019S Patients with PD. J. Mol. Neurosci. 47, 139–143 (2012)
    Article CAS Google Scholar
29. Thaler, A., Mirelman, A., Gurevich, T., Simon, E., Orr-Urtreger, A., Marder, K., Bressman, S. & Giladi, N. Lower cognitive performance in healthy G2019S LRRK2 mutation carriers. Neurology 79, 1027–1032 (2012)
    Article CAS Google Scholar
30. Tiscornia, G., Vivas, E. L. & Belmonte, J. C. Diseases in a dish: modeling human genetic disorders using induced pluripotent cells. Nature Med. 17, 1570–1576 (2011)
    Article CAS Google Scholar

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Acknowledgements

We would like to thank K. Mitani, P. Ng, A. Lieber, Y. Imai, M. A. Miyawaki, Filocamo, S. Goldwurm, Telethon Genetic Biobank Network for providing constructs and cells (the fibroblast samples were obtained from the “Cell Line and DNA Biobank from patients affected by Genetic Diseases” (G. Gaslini Institute)-Telethon Genetic Biobank Network (project no. GTB07001)); Neurological Tissue Bank of the Biobank-Hospital Clínic-IDIBAPS for providing human brain tissue; F. Gage, M. Hetzer, J. Yao, Y. Mu, D. Yu, E. Gelpí, X. M. Wang, X. Wang, G. Bai and Z. J. Liu for helpful discussions; M. Joens and J. Fitzpatrick of the Waitt Advanced Biophotonics Core Facility for performing TEM analysis; M. Marti for imaging, teratoma and karyotyping analysis; F. Osakada for statistics analysis; and M. Schwarz, P. Schwarz and L. Laricchia-Robbio for administrative help. G.-H.L. is supported by the Thousand Young Talents program of China, the National Laboratory of Biomacromolecules, the Strategic Priority Research Program of the Chinese Academy of Sciences, the National Natural Science Foundation of China (NSFC) (81271266 and 31222039), and the Beijing Municipal Natural Science Foundation. J.Q. was partly supported by an AFAR/Ellison Medical Foundation postdoctoral fellowship. K.S. was partly supported by a Uehara Memorial Foundation research fellowship. E.N. was partly supported by an F.M. Kirby Foundation postdoctoral fellowship. X.X. is supported by NSFC (31201111). B.R. was supported by a US National Institute of Health (NIH) grant (ES017166) and the Ludwig Institute for Cancer Research. J.Y. was supported by an NIH grant (P41 RR011823). J.C.I.B. was supported by grants from the Glenn Foundation, G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi, the California Institute of Regenerative Medicine, the Ellison Medical Foundation, the Helmsley Charitable Trust, ERA-Net Neuron, MINECO and Fundacion Cellex.

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Author notes

1. Guang-Hui Liu, Jing Qu and Keiichiro Suzuki: These authors contributed equally to this work.

Authors and Affiliations

1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
   Guang-Hui Liu, Jing Qu, Xiuling Xu, Weiqi Zhang & Ying Li
2. Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ,
   Guang-Hui Liu, Jing Qu, Keiichiro Suzuki, Emmanuel Nivet, Mo Li, Fei Yi, Sergio Ruiz, April Goebl, Jessica Kim, Rupa Devi Soligalla, Ilir Dubova, Concepcion Rodriguez Esteban, Ignacio Sancho-Martinez & Juan Carlos Izpisua Belmonte
3. Center for Regenerative Medicine in Barcelona, Doctor Aiguader 88, 08003 Barcelona, Spain ,
   Nuria Montserrat & Juan Carlos Izpisua Belmonte
4. Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego School of Medicine, La Jolla, 92093-0653, California, USA
   Ulrich Wagner, Audrey Kim & Bing Ren
5. Department of Cell Biology, Scripps Research Institute, La Jolla, 92037, California, USA
   James Thompson & John Yates III

Authors

1. Guang-Hui Liu
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2. Jing Qu
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3. Keiichiro Suzuki
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4. Emmanuel Nivet
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5. Mo Li
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6. Nuria Montserrat
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7. Fei Yi
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8. Xiuling Xu
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9. Sergio Ruiz
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10. Weiqi Zhang
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11. Ulrich Wagner
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12. Audrey Kim
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13. Bing Ren
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14. Ying Li
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15. April Goebl
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16. Jessica Kim
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17. Rupa Devi Soligalla
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18. Ilir Dubova
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19. James Thompson
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20. John Yates III
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21. Concepcion Rodriguez Esteban
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22. Ignacio Sancho-Martinez
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23. Juan Carlos Izpisua Belmonte
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Contributions

G.-H.L., J.Q., K.S. prepared the figures, designed and performed all in vitro experiments. E.N. and N.M. designed and performed in vivo experiments. A.G., J.K., R.D.S., X.X., W.Z., Y.L., S.R. and C.R.E. provided technical assistance. I.D. performed teratoma studies. F.Y. generated microarray data. M.L. performed FISH and DNA methylation assays. B.R., U.W. and A.K. performed and analysed epigenetic studies. J.T. and J.Y.III performed proteomic studies. G.-H.L., J.Q., K.S., E.N., I.S.-M. and J.C.I.B. wrote the manuscript.

Corresponding authors

Correspondence toGuang-Hui Liu or Juan Carlos Izpisua Belmonte.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Figures 1-18 and Supplementary references. (PDF 3162 kb)

Supplementary Data

This file contains Supplementary Tables 1-5. (XLS 135 kb)

In-1 mediated restoration of cellular morphology

The In-1 mediated restoration of cellular morphology in late passage LRRK2 G2019S NSCs. 5 mM In-1 was added to passage 18 ipsNSCs-LK2(GS/GS), and then the cells were cultured for 5 days. Cells were imaged every 10 min for the 5 day duration. (MOV 18568 kb)

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Liu, GH., Qu, J., Suzuki, K. et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.Nature 491, 603–607 (2012). https://doi.org/10.1038/nature11557

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• Received: 25 November 2011
• Accepted: 31 August 2012
• Published: 17 October 2012
• Issue Date: 22 November 2012
• DOI: https://doi.org/10.1038/nature11557