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Int. J. Mol. Sci. 2017, 18(5), 955; doi:10.3390/ijms18050955

Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses

1
National Institute for Health and Welfare, Genomics and Biomarkers Unit, P.O. Box 104, 00251 Helsinki, Finland
2
Folkhälsan Institute of Genetics, P.O. Box 63, University of Helsinki, 00014 Helsinki, Finland
3
Institute for Molecular Medicine Finland, FIMM, Tukholmankatu 8, 00290 Helsinki, Finland
4
Department of Anatomy, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland
These authors contributed equally to the work.
*
Author to whom correspondence should be addressed.
Academic Editor: Ritva Tikkanen
Received: 17 February 2017 / Revised: 12 April 2017 / Accepted: 26 April 2017 / Published: 1 May 2017
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Abstract

Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late infantile variant form of NCL. These CLN5 patient-derived iPSCs (CLN5Y392X iPSCs) harbouring the most common CLN5 mutation, c.1175_1176delAT (p.Tyr392X), were further differentiated into neural lineage cells, the most affected cell type in NCLs. The CLN5Y392X iPSC-derived neural lineage cells showed accumulation of autofluorescent storage material and subunit C of the mitochondrial ATP synthase, both representing the hallmarks of many forms of NCLs, including CLN5 disease. In addition, we detected abnormalities in the intracellular organelles and aberrations in neuronal sphingolipid transportation, verifying the previous findings obtained from Cln5-deficient mouse macrophages. Therefore, patient-derived iPSCs provide a suitable model to study the mechanisms of NCL diseases. View Full-Text
Keywords: CLN5; iPS cells; NCL; sphingolipid; lysosomal storage disease CLN5; iPS cells; NCL; sphingolipid; lysosomal storage disease
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MDPI and ACS Style

Uusi-Rauva, K.; Blom, T.; von Schantz-Fant, C.; Blom, T.; Jalanko, A.; Kyttälä, A. Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses. Int. J. Mol. Sci. 2017, 18, 955.

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