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000140517 037__ $$aDZNE-2020-06839
000140517 041__ $$aEnglish
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000140517 1001_ $$0P:(DE-HGF)0$$aWeykopf, Beatrice$$b0
000140517 245__ $$aInduced pluripotent stem cell-based modeling of mutant LRRK2-associated Parkinson's disease.
000140517 260__ $$aOxford [u.a.]$$bBlackwell$$c2019
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000140517 520__ $$aRecent advances in cell reprogramming have enabled assessment of disease-related cellular traits in patient-derived somatic cells, thus providing a versatile platform for disease modeling and drug development. Given the limited access to vital human brain cells, this technology is especially relevant for neurodegenerative disorders such as Parkinson's disease (PD) as a tool to decipher underlying pathomechanisms. Importantly, recent progress in genome-editing technologies has provided an ability to analyze isogenic induced pluripotent stem cell (iPSC) pairs that differ only in a single genetic change, thus allowing a thorough assessment of the molecular and cellular phenotypes that result from monogenetic risk factors. In this review, we summarize the current state of iPSC-based modeling of PD with a focus on leucine-rich repeat kinase 2 (LRRK2), one of the most prominent monogenetic risk factors for PD linked to both familial and idiopathic forms. The LRRK2 protein is a primarily cytosolic multi-domain protein contributing to regulation of several pathways including autophagy, mitochondrial function, vesicle transport, nuclear architecture and cell morphology. We summarize iPSC-based studies that contributed to improving our understanding of the function of LRRK2 and its variants in the context of PD etiopathology. These data, along with results obtained in our own studies, underscore the multifaceted role of LRRK2 in regulating cellular homeostasis on several levels, including proteostasis, mitochondrial dynamics and regulation of the cytoskeleton. Finally, we expound advantages and limitations of reprogramming technologies for disease modeling and drug development and provide an outlook on future challenges and expectations offered by this exciting technology.
000140517 536__ $$0G:(DE-HGF)POF3-344$$a344 - Clinical and Health Care Research (POF3-344)$$cPOF3-344$$fPOF III$$x0
000140517 542__ $$2Crossref$$i2019-02-25$$uhttp://creativecommons.org/licenses/by-nc/4.0/
000140517 542__ $$2Crossref$$i2019-02-01$$uhttp://doi.wiley.com/10.1002/tdm_license_1.1
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000140517 650_2 $$2MeSH$$aHumans
000140517 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells
000140517 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
000140517 650_2 $$2MeSH$$aMitophagy
000140517 650_2 $$2MeSH$$aModels, Neurological
000140517 650_2 $$2MeSH$$aParkinson Disease: genetics
000140517 650_2 $$2MeSH$$aParkinson Disease: therapy
000140517 7001_ $$aHaupt, Simone$$b1
000140517 7001_ $$0P:(DE-HGF)0$$aJungverdorben, Johannes$$b2
000140517 7001_ $$aFlitsch, Lea Jessica$$b3
000140517 7001_ $$0P:(DE-HGF)0$$aHebisch, Matthias$$b4
000140517 7001_ $$aLiu, Guang-Hui$$b5
000140517 7001_ $$aSuzuki, Keiichiro$$b6
000140517 7001_ $$aBelmonte, Juan Carlos Izpisua$$b7
000140517 7001_ $$0P:(DE-2719)9000249$$aPeitz, Michael$$b8$$udzne
000140517 7001_ $$aBlaess, Sandra$$b9
000140517 7001_ $$0P:(DE-HGF)0$$aTill, Andreas$$b10$$eCorresponding author
000140517 7001_ $$0P:(DE-HGF)0$$aBrüstle, Oliver$$b11
000140517 77318 $$2Crossref$$3journal-article$$a10.1111/ejn.14345$$b : Wiley, 2019-02-01$$n4$$p561-589$$tEuropean Journal of Neuroscience$$v49$$x0953-816X$$y2019
000140517 773__ $$0PERI:(DE-600)2005178-5$$a10.1111/ejn.14345$$gVol. 49, no. 4, p. 561 - 589$$n4$$p561-589$$q49:4<561 - 589$$tEuropean journal of neuroscience$$v49$$x0953-816X$$y2019
000140517 909CO $$ooai:pub.dzne.de:140517$$pVDB
000140517 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)9000249$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b8$$kDZNE
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.tins.2006.03.006$$o10.1016/j.tins.2006.03.006
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1523/JNEUROSCI.1457-18.2018$$o10.1523/JNEUROSCI.1457-18.2018
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1523/JNEUROSCI.3314-15.2016$$o10.1523/JNEUROSCI.3314-15.2016
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1523/JNEUROSCI.4029-08.2009$$o10.1523/JNEUROSCI.4029-08.2009
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.cell.2011.06.001$$o10.1016/j.cell.2011.06.001
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1073/pnas.1520335113$$o10.1073/pnas.1520335113
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1523/JNEUROSCI.0628-16.2016$$o10.1523/JNEUROSCI.0628-16.2016
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1212/WNL.38.8.1285$$o10.1212/WNL.38.8.1285
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/brain/awh510$$o10.1093/brain/awh510
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nrn3961$$o10.1038/nrn3961
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.stem.2015.09.001$$o10.1016/j.stem.2015.09.001
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1523/JNEUROSCI.17-15-05891.1997$$o10.1523/JNEUROSCI.17-15-05891.1997
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1371/journal.pone.0077198$$o10.1371/journal.pone.0077198
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1097/01.jnen.0000235121.98052.54$$o10.1097/01.jnen.0000235121.98052.54
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.stem.2013.11.006$$o10.1016/j.stem.2013.11.006
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.stemcr.2017.03.010$$o10.1016/j.stemcr.2017.03.010
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nature03663$$o10.1038/nature03663
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.stem.2011.01.013$$o10.1016/j.stem.2011.01.013
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1073/pnas.1717590115$$o10.1073/pnas.1717590115
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nprot.2017.078$$o10.1038/nprot.2017.078
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1242/dev.02879$$o10.1242/dev.02879
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nn.3350$$o10.1038/nn.3350
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.stem.2015.07.017$$o10.1016/j.stem.2015.07.017
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nature10202$$o10.1038/nature10202
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nn.3636$$o10.1038/nn.3636
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/srep06330$$o10.1038/srep06330
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1073/pnas.0404700101$$o10.1073/pnas.0404700101
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1073/pnas.1105135108$$o10.1073/pnas.1105135108
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s00441-017-2759-9$$o10.1007/s00441-017-2759-9
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.15252/embj.201798099$$o10.15252/embj.201798099
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.scr.2017.08.013$$o10.1016/j.scr.2017.08.013
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1371/journal.pone.0179082$$o10.1371/journal.pone.0179082
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1371/journal.pone.0059252$$o10.1371/journal.pone.0059252
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1002/stem.1854$$o10.1002/stem.1854
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1186/s13024-016-0140-1$$o10.1186/s13024-016-0140-1
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1155/2016/7351985$$o10.1155/2016/7351985
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/S1474-4422(11)70175-2$$o10.1016/S1474-4422(11)70175-2
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1371/journal.pgen.1004432$$o10.1371/journal.pgen.1004432
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1186/s12974-015-0449-7$$o10.1186/s12974-015-0449-7
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1186/1742-2094-11-52$$o10.1186/1742-2094-11-52
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.cell.2013.11.009$$o10.1016/j.cell.2013.11.009
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000140517 999C5 $$2Crossref$$oSandor C. 2017$$y2017
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nature11859$$o10.1038/nature11859
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.stemcr.2017.10.010$$o10.1016/j.stemcr.2017.10.010
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1523/JNEUROSCI.4441-10.2011$$o10.1523/JNEUROSCI.4441-10.2011
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.stemcr.2015.02.019$$o10.1016/j.stemcr.2015.02.019
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1073/pnas.1522872114$$o10.1073/pnas.1522872114
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1523/JNEUROSCI.2712-13.2014$$o10.1523/JNEUROSCI.2712-13.2014
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/hmg/ddv628$$o10.1093/hmg/ddv628
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/hmg/ddt600$$o10.1093/hmg/ddt600
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nbt.3124$$o10.1038/nbt.3124
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s00441-018-2814-1$$o10.1007/s00441-018-2814-1
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/hmg/ddt301$$o10.1093/hmg/ddt301
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.bbrc.2016.12.188$$o10.1016/j.bbrc.2016.12.188
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nrg3563$$o10.1038/nrg3563
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.cell.2007.11.019$$o10.1016/j.cell.2007.11.019
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.cell.2006.07.024$$o10.1016/j.cell.2006.07.024
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nrm.2016.8$$o10.1038/nrm.2016.8
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1073/pnas.1303829110$$o10.1073/pnas.1303829110
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1111/jnc.13696$$o10.1111/jnc.13696
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000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/s41593-018-0075-7$$o10.1038/s41593-018-0075-7
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nature08797$$o10.1038/nature08797
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1074/jbc.M801992200$$o10.1074/jbc.M801992200
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.nbd.2015.11.002$$o10.1016/j.nbd.2015.11.002
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1111/febs.13305$$o10.1111/febs.13305
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/hmg/dds003$$o10.1093/hmg/dds003
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/hmg/ddl471$$o10.1093/hmg/ddl471
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1001/jamaneurol.2017.0469$$o10.1001/jamaneurol.2017.0469
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.celrep.2014.10.023$$o10.1016/j.celrep.2014.10.023
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s00401-013-1105-x$$o10.1007/s00401-013-1105-x
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1002/stem.1152$$o10.1002/stem.1152
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/cddis.2014.184$$o10.1038/cddis.2014.184
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1126/science.aaf2669$$o10.1126/science.aaf2669
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.bbamcr.2017.09.001$$o10.1016/j.bbamcr.2017.09.001
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/hmg/ddx132$$o10.1093/hmg/ddx132
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.tins.2003.08.009$$o10.1016/j.tins.2003.08.009
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s12035-014-8787-5$$o10.1007/s12035-014-8787-5
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.neuron.2013.05.029$$o10.1016/j.neuron.2013.05.029
000140517 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.neuron.2004.11.005$$o10.1016/j.neuron.2004.11.005