Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway

Xenia Lojewski, John F. Staropoli, Sunita Biswas-legrand, Alexandra M. Simas, Larissa Haliw, Martin K. Selig, Scott H. Coppel, Kendrick A. Goss, Anton Petcherski, Uma Chandrachud, Steven D. Sheridan, Diane Lucente, Katherine B. Sims, James F. Gusella, Dolan Sondhi, Ronald Crystal, Peter Reinhardt, Jared Sterneckert, Hans Schöler, Stephen J. HaggartyAlexander Storch, Andreas Hermann, Susan L. Cotman

Research output: Contribution to journalArticle

62 Citations (Scopus)


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.

Original languageEnglish
Article numberddt596
Pages (from-to)2005-2022
Number of pages18
JournalHuman Molecular Genetics
Issue number8
Publication statusPublished - 1 Apr 2014
Externally publishedYes


ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Lojewski, X., Staropoli, J. F., Biswas-legrand, S., Simas, A. M., Haliw, L., Selig, M. K., Coppel, S. H., Goss, K. A., Petcherski, A., Chandrachud, U., Sheridan, S. D., Lucente, D., Sims, K. B., Gusella, J. F., Sondhi, D., Crystal, R., Reinhardt, P., Sterneckert, J., Schöler, H., ... Cotman, S. L. (2014). Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway. Human Molecular Genetics, 23(8), 2005-2022. [ddt596].