Publication Type	Academic Article
Authors	Lojewski X, Staropoli J, Biswas-Legrand S, Simas A, Haliw L, Selig M, Coppel S, Goss K, Petcherski A, Chandrachud U, Sheridan S, Lucente D, Sims K, Gusella J, Sondhi D, Crystal R, Reinhardt P, Sterneckert J, Schöler H, Haggarty S, Storch A, Hermann A, Cotman S
Journal	Hum Mol Genet
Volume	23
Issue	8
Pagination	2005-22
Date Published	11/23/2013
ISSN	1460-2083
Keywords	Aminopeptidases, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Induced Pluripotent Stem Cells, Membrane Glycoproteins, Models, Neurological, Molecular Chaperones, Mutation, Neuronal Ceroid-Lipofuscinoses, Serine Proteases
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.
DOI	10.1093/hmg/ddt596
PubMed ID	24271013
PubMed Central ID	PMC3959814