Progressive degeneration of human neural stem cells caused by pathogenic LRRK2
Open accessAbstract
Nuclear-architecture defects have been shown to correlate with the manifestation of a number of human diseases as well as ageing. It is therefore plausible that diseases whose manifestations correlate with ageing might be connected to the appearance of nuclear aberrations over time. We decided to evaluate nuclear organization in the context of ageing-associated disorders by focusing on a leucine-rich repeat kinase 2 (LRRK2) dominant mutation (G2019S; glycine-to-serine substitution at amino acid 2019), which is associated with familial and sporadic Parkinson's disease as well as impairment of adult neurogenesis in mice. Here we report on the generation of induced pluripotent stem cells (iPSCs) derived from Parkinson's disease patients and the implications of LRRK2(G2019S) mutation in human neural-stem-cell (NSC) populations. Mutant NSCs showed increased susceptibility to proteasomal stress as well as passage-dependent deficiencies in nuclear-envelope organization, clonal expansion and neuronal differentiation. Disease phenotypes were rescued by targeted correction of the LRRK2(G2019S) mutation with its wild-type counterpart in Parkinson's disease iPSCs and were recapitulated after targeted knock-in of the LRRK2(G2019S) mutation in human embryonic stem cells. Analysis of human brain tissue showed nuclear-envelope impairment in clinically diagnosed Parkinson's disease patients. Together, our results identify the nucleus as a previously unknown cellular organelle in Parkinson's disease pathology and may help to open new avenues for Parkinson's disease diagnoses as well as for the potential development of therapeutics targeting this fundamental cell structure.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Homozygous WRN null ESC lines were successfully generated.
“we successfully generated homozygous WRN null ESC lines (ESCs-WRN−/−)”
From A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging (2015) · cites this paper as [10]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Lamin A-Dependent Nuclear Defects in Human Aging
Scaffidi, P., & Misteli, T. (2006) · Science · doi:10.1126/science.1127168 · Cited by 1,224 · see citing works
Dechat, T., Pfleghaar, K., Sengupta, K., Shimi, T., Shumaker, D. K., Solimando, L., & Goldman, R. D. (2008) · Genes & Development · doi:10.1101/gad.1652708 · Cited by 1,001 · see citing works
Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome
Liu, G.-H., Barkho, B. Z., Ruiz, S., Diep, D., Qu, J., Yang, S.-L., Panopoulos, A. D., Suzuki, K., Kurian, L., Walsh, C., et al. (2011) · Nature · doi:10.1038/nature09879 · Cited by 575 · see citing works
Self-citationThe role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease
Cookson, M. (2010) · Nature reviews. Neuroscience · doi:10.1038/nrn2935 · Cited by 542 · see citing works
Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2
Deng, X., Dzamko, N. L., Prescott, A. R., Davies, P., Liu, Q., Yang, Q., Lee, J., Patricelli, M. P., Nomanbhoy, T. K., Alessi, D. R., et al. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.538 · Cited by 424 · see citing works
Lamin B1 duplications cause autosomal dominant leukodystrophy
Padiath, Q. S., Saigoh, K., Schiffmann, R., Asahara, H., Yamada, T., Koeppen, A. H., Hogan, K. J., Ptáček, L. J., & Fu, Y. (2006) · Nature Genetics · doi:10.1038/ng1872 · Cited by 407 · see citing works
Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression
Gehrke, S., Imai, Y., Sokol, N. S., & Lu, B. (2010) · Nature · doi:10.1038/nature09191 · Cited by 398 · see citing works
Nichols, R. J., Dzamko, N. L., Morrice, N. A., Campbell, D. G., Deák, M., Ordureau, A., Macartney, T., Tong, Y., Shen, J., Prescott, A. R., et al. (2010) · Biochemical Journal · doi:10.1042/bj20100483 · Cited by 390 · see citing works
Dzamko, N. L., Deák, M., Hentati, F., Reith, A. D., Prescott, A. R., Alessi, D. R., & Nichols, R. J. (2010) · Biochemical Journal · doi:10.1042/bj20100784 · Cited by 379 · see citing works
Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease
Lee, B. D., Shin, J., VanKampen, J., Petrucelli, L., West, A. B., Ko, H. S., Lee, Y.-I., Maguire‐Zeiss, K. A., Bowers, W. J., Federoff, H. J., et al. (2010) · Nature Medicine · doi:10.1038/nm.2199 · Cited by 376 · see citing works
Li, W., Sun, W., Zhang, Y., Wei, W., Ambasudhan, R., Xia, P., Talantova, M. V., Lin, T., Kim, J., Wang, X., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014041108 · Cited by 375 · see citing works
Self-citationWerner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases
Kudlow, B. A., Kennedy, B. K., & Monnat, R. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2161 · Cited by 304 · see citing works
Diseases of the Nuclear EnvelopePreprint
Worman, H. J., Östlund, C., & Wang, Y. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000760 · Cited by 236 · see citing works
Krishnan, V., Chow, M. Z. Y., Wang, Z., Zhang, L., Liu, B., Liu, X., & Zhou, Z. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102789108 · Cited by 236 · see citing works
Cheung, I., Shulha, H. P., Jiang, Y., Matevossian, A., Wang, J., Weng, Z., & Akbarian, S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001702107 · Cited by 235 · see citing works
Coffinier, C., Jung, H.-J., Nobumori, C., Chang, S., Tu, Y., Barnes, R. H., Yoshinaga, Y., de Jong, P. J., Vergnes, L., Reue, K., et al. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-06-0504 · Cited by 225 · see citing works
Targeted Gene Correction of Laminopathy-Associated LMNA Mutations in Patient-Specific iPSCs
Liu, G., Suzuki, K., Qu, J. T., Sancho-Martinez, I., Yi, F., Li, M., Kumar, S., Nivet, E., Kim, J., Soligalla, R. D., et al. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.04.019 · Cited by 219 · see citing works
Self-citationDiseases in a dish: modeling human genetic disorders using induced pluripotent cells
Tiscórnia, G., Lorenzo-Vivas, E., & Belmonte, J. C. I. (2011) · Nature Medicine · doi:10.1038/nm.2504 · Cited by 204 · see citing works
Self-citationAdult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice
Winner, B., Melrose, H. L., Zhao, C. N., Hinkle, K. M., Yue, M., Kent, C., Braithwaite, A. T., Ogholikhan, S., Aigner, R., Winkler, J., et al. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.12.008 · Cited by 183 · see citing works
Parkinson's disease: insights from pathways
Cookson, M., & Bandmann, O. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq167 · Cited by 162 · see citing works
Suzuki, K., Mitsui, K., Aizawa, E., Hasegawa, K., Kawase, E., Yamagishi, T., Shimizu, Y., Suemori, H., Nakatsuji, N., & Mitani, K. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806976105 · Cited by 108 · see citing works
Self-citationProteasome inhibition modeling nigral neuron degeneration in Parkinson’s disease
Xie, W., Li, X., Li, C., Zhu, W., Jankovic, J. J., & Le, W. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06914.x · Cited by 105 · see citing works
Kanao, T., Venderová, K., Park, D. S., Unterman, T. G., Lu, B., & Imai, Y. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq289 · Cited by 91 · see citing works
Abnormalities of the nucleus and nuclear inclusions in neurodegenerative disease: a work in progress
Woulfe, J. (2007) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2006.00819.x · Cited by 88 · see citing works
Nuclear envelope dispersion triggered by deregulated Cdk5 precedes neuronal death
Chang, K., Multani, P. S., Sun, K.-H., Vincent, F., de Pablo, Y., Ghosh, S., Gupta, R., Lee, H.-P., Lee, H., Smith, M. A., et al. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-07-0654 · Cited by 76 · see citing works
Li, M., Suzuki, K., Qu, J. T., et al. (2011) · Cell Research · doi:10.1038/cr.2011.186 · Cited by 67 · see citing works
Self-citationRudenko, I. N., Chia, R., & Cookson, M. (2012) · BMC Medicine · doi:10.1186/1741-7015-10-20 · Cited by 64 · see citing works
Lower cognitive performance in healthy G2019S LRRK2 mutation carriers
Thaler, A., Mirelman, A., Gurevich, T., Simon, E. S., Orr‐Urtreger, A., Marder, K. S., Bressman, S., Giladi, N., Bressman, S., Saunders-Pullman, R. J., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e3182684646 · Cited by 63 · see citing works
Amyotrophic Lateral Sclerosis Mutant VAPB Causes a Nuclear Envelope Defect
Tran, D., Chalhoub, A., Schooley, A., et al. (2012) · Journal of Cell Science · doi:10.1242/jcs.102111 · Cited by 47 · see citing works
Aizawa, E., Hirabayashi, Y., Iwanaga, Y., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2011.266 · Cited by 47 · see citing works
Clinical and Pathological Characteristics of LRRK2 G2019S Patients with PD
Poulopoulos, M., Cortes, E. P., Vonsattel, J.-P. G., et al. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-011-9696-y · Cited by 43 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Induced pluripotent stem cell technology: a decade of progress.
Shi, Y., Inoue, H., Wu, J. C., & Yamanaka, S. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.245 · Cited by 1,525 · see citing works
Autophagy and apoptosis dysfunction in neurodegenerative disorders
Ghavami, S., Shojaei, S., Yeganeh, B., Ande, S. R., Jangamreddy, J. R., Mehrpour, M., Christoffersson, J., Chaabane, W., Moghadam, A. R., Kashani, H. H., et al. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.10.004 · Cited by 1,039 · see citing works
Human iPSC-based modeling of late-onset disease via progerin-induced aging
Miller, J. D., Ganat, Y. M., Kishinevsky, S., Bowman, R. L., Liu, B., Tu, E. Y., Mandal, P. K., Vera, E., Shim, J.-W., Kriks, S., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.11.006 · Cited by 777 · see citing works
Raja, W. K., Mungenast, A. E., Lin, Y.-T., Ko, T., Abdurrob, F., Seo, J., & Tsai, L.-H. (2016) · PLOS ONE · doi:10.1371/journal.pone.0161969 · Cited by 569 · see citing works
A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging
Zhang, W., Li, J., Suzuki, K., Qu, J., Wang, P., Zhou, J., Liu, X., Ren, R., Xu, X., Ocampo, A., et al. (2015) · Science · doi:10.1126/science.aaa1356 · Cited by 551 · see citing works
Self-citationModeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure
Chen, X., Sun, G., Tian, E., Zhang, M., Davtyan, H., Beach, T. G., Reiman, E. M., Blurton‐Jones, M., Holtzman, D. M., & Shi, Y. (2021) · Advanced Science · doi:10.1002/advs.202101462 · Cited by 200 · see citing works
Suzuki, K., Yu, C., Qu, J., Li, M., Yao, X., Yuan, T., Goebl, A., Tang, S., Ren, R., Aizawa, E., et al. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.06.016 · Cited by 169 · see citing works
Self-citationSchildknecht, S., Gerding, H. R., Karreman, C., Drescher, M., Lashuel, H. A., Outeiro, T. F., Di Monte, D. A., & Leist, M. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12226 · Cited by 148 · see citing works
D’Aiuto, L., Zhi, Y., Kumar Das, D., Wilcox, M. R., Johnson, J. W., McClain, L., MacDonald, M. L., Di Maio, R., Schurdak, M. E., Piazza, P., et al. (2014) · Organogenesis · doi:10.1080/15476278.2015.1011921 · Cited by 131 · see citing works
Li, L., Chao, J., & Shi, Y. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2713-x · Cited by 89 · see citing works
Qiang, L., Fujita, R., & Abeliovich, A. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.002 · Cited by 59 · see citing works
Elanzew, A., Nießing, B., Langendoerfer, D., Rippel, O., Piotrowski, T., Schenk, F., Kulik, M., Peitz, M., Breitkreuz, Y., Jung, S., et al. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.580352 · Cited by 47 · see citing works
Hippocampal proliferation is increased in presymptomatic Parkinson’s disease and due to microglia
Doorn, K. J., Drukarch, B., van Dam, A.-M., & Lucassen, P. J. (2014) · Neural Plasticity · doi:10.1155/2014/959154 · Cited by 24 · see citing works
- Authors
- Liu, G.-H., Qu, J., Suzuki, K., Nivet, E., Li, M., Montserrat, N., Yi, F., Xu, X., Ruiz, S., Zhang, W., Wagner, U., Kim, A., Ren, B., Li, Y., Goebl, A., Kim, J., Soligalla, R. D., Dubova, I., Thompson, J., III, J. Y., Esteban, C. R., Sancho-Martinez, I., & Belmonte, J. C. I.
- Affiliations
- Salk Institute for Biological Studies (US)
- Chinese Academy of Sciences (CN)
- University of California San Diego (US)
- Scripps Research Institute (US)
- Corresponding author
- Liu, Guang-Hui
- ORCID
- Venue
- Nature
- Published
- 2012-10-17
- Volume
- 491
- Issue
- 7425
- Pages
- 603-607
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3504651
- OpenAlex
- W2088778610
- Cited by
- 339
- References
- 31
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 19 · 2023: 14 · 2022: 24 · 2021: 15 · 2020: 38 · 2019: 28 · 2018: 21 · 2017: 27 · 2016: 36 · 2015: 28 · 2014: 28 · 2013: 34 · 2012: 6
- FWCI
- 19.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL AMU (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (P41GM103533)
- National Institute of Environmental Health Sciences (U01ES017166, ES017166)
- National Center for Research Resources (P41RR011823)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- Parkinson's disease, LRRK2, G2019S mutation, neural stem cells, nuclear envelope, nuclear organization, induced pluripotent stem cells, clonal expansion, neuronal differentiation, human brain tissue
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Cell Differentiation, Cell Division, Cell Line, Clone Cells, Humans, Mutation, Nuclear Envelope, Parkinson Disease, Stress, Physiological, Apoptosis, Protein Serine-Threonine Kinases, Proteasome Endopeptidase Complex, Mutant Proteins, Embryonic Stem Cells, Gene Knock-In Techniques, Induced Pluripotent Stem Cells, Neural Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
