TY  - JOUR
AU  - Lojewski, Xenia
AU  - Staropoli, John F
AU  - Biswas-Legrand, Sunita
AU  - Simas, Alexandra M
AU  - Haliw, Larissa
AU  - Selig, Martin K
AU  - Coppel, Scott H
AU  - Goss, Kendrick A
AU  - Petcherski, Anton
AU  - Chandrachud, Uma
AU  - Sheridan, Steven D
AU  - Lucente, Diane
AU  - Sims, Katherine B
AU  - Gusella, James F
AU  - Sondhi, Dolan
AU  - Crystal, Ronald G
AU  - Reinhardt, Peter
AU  - Sterneckert, Jared
AU  - Schöler, Hans
AU  - Haggarty, Stephen J
AU  - Storch, Alexander
AU  - Hermann, Andreas
AU  - Cotman, Susan L
TI  - Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway.
JO  - Human molecular genetics
VL  - 23
IS  - 8
SN  - 1460-2083
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2020-03643
SP  - 2005-2022
PY  - 2014
AB  - 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.
KW  - Aminopeptidases: genetics
KW  - Aminopeptidases: metabolism
KW  - Blotting, Western
KW  - Case-Control Studies
KW  - Cell Proliferation
KW  - Cells, Cultured
KW  - Dipeptidyl-Peptidases and Tripeptidyl-Peptidases: genetics
KW  - Dipeptidyl-Peptidases and Tripeptidyl-Peptidases: metabolism
KW  - Electrophysiology
KW  - Endoplasmic Reticulum: drug effects
KW  - Endoplasmic Reticulum: metabolism
KW  - Fenofibrate: pharmacology
KW  - Fibroblasts: drug effects
KW  - Fibroblasts: metabolism
KW  - Fibroblasts: pathology
KW  - Gemfibrozil: pharmacology
KW  - Golgi Apparatus: drug effects
KW  - Golgi Apparatus: metabolism
KW  - Humans
KW  - Immunoenzyme Techniques
KW  - Induced Pluripotent Stem Cells: drug effects
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: pathology
KW  - Lysosomes: drug effects
KW  - Lysosomes: metabolism
KW  - Membrane Glycoproteins: genetics
KW  - Membrane Glycoproteins: metabolism
KW  - Models, Neurological
KW  - Molecular Chaperones: genetics
KW  - Molecular Chaperones: metabolism
KW  - Mutation: genetics
KW  - Neuronal Ceroid-Lipofuscinoses: genetics
KW  - Neuronal Ceroid-Lipofuscinoses: metabolism
KW  - Neuronal Ceroid-Lipofuscinoses: pathology
KW  - Neurons: drug effects
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Serine Proteases: genetics
KW  - Serine Proteases: metabolism
KW  - CLN3 protein, human (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Molecular Chaperones (NLM Chemicals)
KW  - Serine Proteases (NLM Chemicals)
KW  - Aminopeptidases (NLM Chemicals)
KW  - Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (NLM Chemicals)
KW  - tripeptidyl-peptidase 1 (NLM Chemicals)
KW  - Gemfibrozil (NLM Chemicals)
KW  - Fenofibrate (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24271013
C2  - pmc:PMC3959814
DO  - DOI:10.1093/hmg/ddt596
UR  - https://pub.dzne.de/record/137321
ER  -