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@ARTICLE{Lojewski:137321,
      author       = {Lojewski, Xenia and Staropoli, John F and Biswas-Legrand,
                      Sunita and Simas, Alexandra M and Haliw, Larissa and Selig,
                      Martin K and Coppel, Scott H and Goss, Kendrick A and
                      Petcherski, Anton and Chandrachud, Uma and Sheridan, Steven
                      D and Lucente, Diane and Sims, Katherine B and Gusella,
                      James F and Sondhi, Dolan and Crystal, Ronald G and
                      Reinhardt, Peter and Sterneckert, Jared and Schöler, Hans
                      and Haggarty, Stephen J and Storch, Alexander and Hermann,
                      Andreas and Cotman, Susan L},
      title        = {{H}uman i{PSC} models of neuronal ceroid lipofuscinosis
                      capture distinct effects of {TPP}1 and {CLN}3 mutations on
                      the endocytic pathway.},
      journal      = {Human molecular genetics},
      volume       = {23},
      number       = {8},
      issn         = {1460-2083},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2020-03643},
      pages        = {2005-2022},
      year         = {2014},
      abstract     = {Neuronal 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.},
      keywords     = {Aminopeptidases: genetics / Aminopeptidases: metabolism /
                      Blotting, Western / Case-Control Studies / Cell
                      Proliferation / Cells, Cultured / Dipeptidyl-Peptidases and
                      Tripeptidyl-Peptidases: genetics / Dipeptidyl-Peptidases and
                      Tripeptidyl-Peptidases: metabolism / Electrophysiology /
                      Endoplasmic Reticulum: drug effects / Endoplasmic Reticulum:
                      metabolism / Fenofibrate: pharmacology / Fibroblasts: drug
                      effects / Fibroblasts: metabolism / Fibroblasts: pathology /
                      Gemfibrozil: pharmacology / Golgi Apparatus: drug effects /
                      Golgi Apparatus: metabolism / Humans / Immunoenzyme
                      Techniques / Induced Pluripotent Stem Cells: drug effects /
                      Induced Pluripotent Stem Cells: metabolism / Induced
                      Pluripotent Stem Cells: pathology / Lysosomes: drug effects
                      / Lysosomes: metabolism / Membrane Glycoproteins: genetics /
                      Membrane Glycoproteins: metabolism / Models, Neurological /
                      Molecular Chaperones: genetics / Molecular Chaperones:
                      metabolism / Mutation: genetics / Neuronal
                      Ceroid-Lipofuscinoses: genetics / Neuronal
                      Ceroid-Lipofuscinoses: metabolism / Neuronal
                      Ceroid-Lipofuscinoses: pathology / Neurons: drug effects /
                      Neurons: metabolism / Neurons: pathology / Serine Proteases:
                      genetics / Serine Proteases: metabolism / CLN3 protein,
                      human (NLM Chemicals) / Membrane Glycoproteins (NLM
                      Chemicals) / Molecular Chaperones (NLM Chemicals) / Serine
                      Proteases (NLM Chemicals) / Aminopeptidases (NLM Chemicals)
                      / Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (NLM
                      Chemicals) / tripeptidyl-peptidase 1 (NLM Chemicals) /
                      Gemfibrozil (NLM Chemicals) / Fenofibrate (NLM Chemicals)},
      cin          = {AG Storch ; AG Storch 2 Rostock / Clinical Dementia
                      Research Rostock /Greifswald ; AG Teipel},
      ddc          = {570},
      cid          = {I:(DE-2719)5000014 / I:(DE-2719)1510100},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24271013},
      pmc          = {pmc:PMC3959814},
      doi          = {10.1093/hmg/ddt596},
      url          = {https://pub.dzne.de/record/137321},
}