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000137321 0247_ $$2doi$$a10.1093/hmg/ddt596
000137321 0247_ $$2pmid$$apmid:24271013
000137321 0247_ $$2pmc$$apmc:PMC3959814
000137321 0247_ $$2ISSN$$a0964-6906
000137321 0247_ $$2ISSN$$a1460-2083
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000137321 037__ $$aDZNE-2020-03643
000137321 041__ $$aEnglish
000137321 082__ $$a570
000137321 1001_ $$aLojewski, Xenia$$b0
000137321 245__ $$aHuman iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway.
000137321 260__ $$aOxford$$bOxford Univ. Press$$c2014
000137321 264_1 $$2Crossref$$3online$$bOxford University Press (OUP)$$c2013-11-23
000137321 264_1 $$2Crossref$$3print$$bOxford University Press (OUP)$$c2014-04-15
000137321 3367_ $$2DRIVER$$aarticle
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000137321 3367_ $$2BibTeX$$aARTICLE
000137321 3367_ $$2ORCID$$aJOURNAL_ARTICLE
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000137321 520__ $$aNeuronal ceroid lipofuscinosis (NCL) comprises ∼13 genetically distinct lysosomal disorders primarily affecting the central nervous system. Here we report successful reprograming of patient fibroblasts into induced pluripotent stem cells (iPSCs) for the two most common NCL subtypes: classic late-infantile NCL, caused by TPP1(CLN2) mutation, and juvenile NCL, caused by CLN3 mutation. CLN2/TPP1- and CLN3-iPSCs displayed overlapping but distinct biochemical and morphological abnormalities within the endosomal-lysosomal system. In neuronal derivatives, further abnormalities were observed in mitochondria, Golgi and endoplasmic reticulum. While lysosomal storage was undetectable in iPSCs, progressive disease subtype-specific storage material was evident upon neural differentiation and was rescued by reintroducing the non-mutated NCL proteins. In proof-of-concept studies, we further documented differential effects of potential small molecule TPP1 activity inducers. Fenofibrate and gemfibrozil, previously reported to induce TPP1 activity in control cells, failed to increase TPP1 activity in patient iPSC-derived neural progenitor cells. Conversely, nonsense suppression by PTC124 resulted in both an increase of TPP1 activity and attenuation of neuropathology in patient iPSC-derived neural progenitor cells. This study therefore documents the high value of this powerful new set of tools for improved drug screening and for investigating early mechanisms driving NCL pathogenesis.
000137321 536__ $$0G:(DE-HGF)POF3-344$$a344 - Clinical and Health Care Research (POF3-344)$$cPOF3-344$$fPOF III$$x0
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000137321 650_7 $$2NLM Chemicals$$aCLN3 protein, human
000137321 650_7 $$2NLM Chemicals$$aMembrane Glycoproteins
000137321 650_7 $$2NLM Chemicals$$aMolecular Chaperones
000137321 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aSerine Proteases
000137321 650_7 $$0EC 3.4.11.-$$2NLM Chemicals$$aAminopeptidases
000137321 650_7 $$0EC 3.4.14.-$$2NLM Chemicals$$aDipeptidyl-Peptidases and Tripeptidyl-Peptidases
000137321 650_7 $$0EC 3.4.14.9$$2NLM Chemicals$$atripeptidyl-peptidase 1
000137321 650_7 $$0Q8X02027X3$$2NLM Chemicals$$aGemfibrozil
000137321 650_7 $$0U202363UOS$$2NLM Chemicals$$aFenofibrate
000137321 650_2 $$2MeSH$$aAminopeptidases: genetics
000137321 650_2 $$2MeSH$$aAminopeptidases: metabolism
000137321 650_2 $$2MeSH$$aBlotting, Western
000137321 650_2 $$2MeSH$$aCase-Control Studies
000137321 650_2 $$2MeSH$$aCell Proliferation
000137321 650_2 $$2MeSH$$aCells, Cultured
000137321 650_2 $$2MeSH$$aDipeptidyl-Peptidases and Tripeptidyl-Peptidases: genetics
000137321 650_2 $$2MeSH$$aDipeptidyl-Peptidases and Tripeptidyl-Peptidases: metabolism
000137321 650_2 $$2MeSH$$aElectrophysiology
000137321 650_2 $$2MeSH$$aEndoplasmic Reticulum: drug effects
000137321 650_2 $$2MeSH$$aEndoplasmic Reticulum: metabolism
000137321 650_2 $$2MeSH$$aFenofibrate: pharmacology
000137321 650_2 $$2MeSH$$aFibroblasts: drug effects
000137321 650_2 $$2MeSH$$aFibroblasts: metabolism
000137321 650_2 $$2MeSH$$aFibroblasts: pathology
000137321 650_2 $$2MeSH$$aGemfibrozil: pharmacology
000137321 650_2 $$2MeSH$$aGolgi Apparatus: drug effects
000137321 650_2 $$2MeSH$$aGolgi Apparatus: metabolism
000137321 650_2 $$2MeSH$$aHumans
000137321 650_2 $$2MeSH$$aImmunoenzyme Techniques
000137321 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: drug effects
000137321 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000137321 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: pathology
000137321 650_2 $$2MeSH$$aLysosomes: drug effects
000137321 650_2 $$2MeSH$$aLysosomes: metabolism
000137321 650_2 $$2MeSH$$aMembrane Glycoproteins: genetics
000137321 650_2 $$2MeSH$$aMembrane Glycoproteins: metabolism
000137321 650_2 $$2MeSH$$aModels, Neurological
000137321 650_2 $$2MeSH$$aMolecular Chaperones: genetics
000137321 650_2 $$2MeSH$$aMolecular Chaperones: metabolism
000137321 650_2 $$2MeSH$$aMutation: genetics
000137321 650_2 $$2MeSH$$aNeuronal Ceroid-Lipofuscinoses: genetics
000137321 650_2 $$2MeSH$$aNeuronal Ceroid-Lipofuscinoses: metabolism
000137321 650_2 $$2MeSH$$aNeuronal Ceroid-Lipofuscinoses: pathology
000137321 650_2 $$2MeSH$$aNeurons: drug effects
000137321 650_2 $$2MeSH$$aNeurons: metabolism
000137321 650_2 $$2MeSH$$aNeurons: pathology
000137321 650_2 $$2MeSH$$aSerine Proteases: genetics
000137321 650_2 $$2MeSH$$aSerine Proteases: metabolism
000137321 7001_ $$aStaropoli, John F$$b1
000137321 7001_ $$aBiswas-Legrand, Sunita$$b2
000137321 7001_ $$aSimas, Alexandra M$$b3
000137321 7001_ $$aHaliw, Larissa$$b4
000137321 7001_ $$aSelig, Martin K$$b5
000137321 7001_ $$aCoppel, Scott H$$b6
000137321 7001_ $$aGoss, Kendrick A$$b7
000137321 7001_ $$aPetcherski, Anton$$b8
000137321 7001_ $$aChandrachud, Uma$$b9
000137321 7001_ $$aSheridan, Steven D$$b10
000137321 7001_ $$aLucente, Diane$$b11
000137321 7001_ $$aSims, Katherine B$$b12
000137321 7001_ $$aGusella, James F$$b13
000137321 7001_ $$aSondhi, Dolan$$b14
000137321 7001_ $$aCrystal, Ronald G$$b15
000137321 7001_ $$aReinhardt, Peter$$b16
000137321 7001_ $$aSterneckert, Jared$$b17
000137321 7001_ $$aSchöler, Hans$$b18
000137321 7001_ $$aHaggarty, Stephen J$$b19
000137321 7001_ $$0P:(DE-2719)9000306$$aStorch, Alexander$$b20$$udzne
000137321 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b21$$udzne
000137321 7001_ $$0P:(DE-HGF)0$$aCotman, Susan L$$b22$$eCorresponding author
000137321 77318 $$2Crossref$$3journal-article$$a10.1093/hmg/ddt596$$b : Oxford University Press (OUP), 2013-11-23$$n8$$p2005-2022$$tHuman Molecular Genetics$$v23$$x1460-2083$$y2013
000137321 773__ $$0PERI:(DE-600)1474816-2$$a10.1093/hmg/ddt596$$gVol. 23, no. 8, p. 2005 - 2022$$n8$$p2005-2022$$q23:8<2005 - 2022$$tHuman molecular genetics$$v23$$x1460-2083$$y2013
000137321 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959814
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