title: Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway.
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.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Xenia
authors.initials: X
authors.lastname: Lojewski
authors.forename: John F
authors.initials: JF
authors.lastname: Staropoli
authors.forename: Sunita
authors.initials: S
authors.lastname: Biswas-Legrand
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Simas
authors.forename: Larissa
authors.initials: L
authors.lastname: Haliw
authors.forename: Martin K
authors.initials: MK
authors.lastname: Selig
authors.forename: Scott H
authors.initials: SH
authors.lastname: Coppel
authors.forename: Kendrick A
authors.initials: KA
authors.lastname: Goss
authors.forename: Anton
authors.initials: A
authors.lastname: Petcherski
authors.forename: Uma
authors.initials: U
authors.lastname: Chandrachud
authors.forename: Steven D
authors.initials: SD
authors.lastname: Sheridan
authors.forename: Diane
authors.initials: D
authors.lastname: Lucente
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Sims
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Dolan
authors.initials: D
authors.lastname: Sondhi
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.forename: Peter
authors.initials: P
authors.lastname: Reinhardt
authors.forename: Jared
authors.initials: J
authors.lastname: Sterneckert
authors.forename: Hans
authors.initials: H
authors.lastname: Schöler
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cotman
mesh_terms: D000626:Aminopeptidases / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics* / Q000378:metabolism; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015248:Gemfibrozil / Q000494:pharmacology; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008959:Models, Neurological; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057057:Serine Proteases / Q000235:genetics* / Q000378:metabolism; D000091346:Tripeptidyl-Peptidase 1
chemical_list: C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human; D015248:Gemfibrozil; D011345:Fenofibrate