Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway
Copyright policy )Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway
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.
- Cornell University United States
- Harvard University United States
- Massachusetts General Hospital United States
- Deutsche Zentren der Gesundheitsforschung Germany
- Max Planck Institute for Molecular Biomedicine Germany
metabolism [Dipeptidyl-Peptidases and Tripeptidyl-Peptidases], Golgi Apparatus, drug effects [Golgi Apparatus], metabolism [Serine Proteases], Endoplasmic Reticulum, Aminopeptidases, genetics [Dipeptidyl-Peptidases and Tripeptidyl-Peptidases], metabolism [Lysosomes], Immunoenzyme Techniques, genetics [Membrane Glycoproteins], Fenofibrate, metabolism [Endoplasmic Reticulum], pathology [Neuronal Ceroid-Lipofuscinoses], pathology [Neurons], drug effects [Lysosomes], metabolism [Molecular Chaperones], genetics [Neuronal Ceroid-Lipofuscinoses], Cells, Cultured, Membrane Glycoproteins, drug effects [Induced Pluripotent Stem Cells], pharmacology [Gemfibrozil], pathology [Induced Pluripotent Stem Cells], metabolism [Induced Pluripotent Stem Cells], Electrophysiology, metabolism [Neurons], tripeptidyl-peptidase 1, genetics [Aminopeptidases], pathology [Fibroblasts], genetics [Serine Proteases], metabolism [Fibroblasts], Blotting, Western, Induced Pluripotent Stem Cells, Models, Neurological, metabolism [Aminopeptidases], CLN3 protein, human, genetics [Mutation], drug effects [Endoplasmic Reticulum], metabolism [Golgi Apparatus], genetics [Molecular Chaperones], drug effects [Neurons], Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Cell Proliferation, drug effects [Fibroblasts], metabolism [Neuronal Ceroid-Lipofuscinoses], pharmacology [Fenofibrate], Fibroblasts, Case-Control Studies, Mutation, Serine Proteases, Gemfibrozil, Lysosomes, metabolism [Membrane Glycoproteins], Molecular Chaperones, ddc: ddc:570
metabolism [Dipeptidyl-Peptidases and Tripeptidyl-Peptidases], Golgi Apparatus, drug effects [Golgi Apparatus], metabolism [Serine Proteases], Endoplasmic Reticulum, Aminopeptidases, genetics [Dipeptidyl-Peptidases and Tripeptidyl-Peptidases], metabolism [Lysosomes], Immunoenzyme Techniques, genetics [Membrane Glycoproteins], Fenofibrate, metabolism [Endoplasmic Reticulum], pathology [Neuronal Ceroid-Lipofuscinoses], pathology [Neurons], drug effects [Lysosomes], metabolism [Molecular Chaperones], genetics [Neuronal Ceroid-Lipofuscinoses], Cells, Cultured, Membrane Glycoproteins, drug effects [Induced Pluripotent Stem Cells], pharmacology [Gemfibrozil], pathology [Induced Pluripotent Stem Cells], metabolism [Induced Pluripotent Stem Cells], Electrophysiology, metabolism [Neurons], tripeptidyl-peptidase 1, genetics [Aminopeptidases], pathology [Fibroblasts], genetics [Serine Proteases], metabolism [Fibroblasts], Blotting, Western, Induced Pluripotent Stem Cells, Models, Neurological, metabolism [Aminopeptidases], CLN3 protein, human, genetics [Mutation], drug effects [Endoplasmic Reticulum], metabolism [Golgi Apparatus], genetics [Molecular Chaperones], drug effects [Neurons], Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Cell Proliferation, drug effects [Fibroblasts], metabolism [Neuronal Ceroid-Lipofuscinoses], pharmacology [Fenofibrate], Fibroblasts, Case-Control Studies, Mutation, Serine Proteases, Gemfibrozil, Lysosomes, metabolism [Membrane Glycoproteins], Molecular Chaperones, ddc: ddc:570
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