Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: Studies of lysosomal storage diseases and channelopathy

S. Kano, M. Yuan, R. A. Cardarelli, G. Maegawa, N. Higurashi, M. Gaval-Cruz, A. M. Wilson, C. Tristan, M. A. Kondo, Y. Chen, M. Koga, C. Obie, K. Ishizuka, S. Seshadri, R. Srivastava, T. A. Kato, Y. Horiuchi, T. W. Sedlak, Y. Lee, J. L. RapoportS. Hirose, H. Okano, D. Valle, P. O’Donnell, A. Sawa, M. Kai

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies.

Original languageEnglish
Pages (from-to)138-145
Number of pages8
JournalCurrent Molecular Medicine
Volume15
Issue number2
DOIs
Publication statusPublished - 2015 Jan 1

Keywords

  • Channelopathy
  • Direct conversion
  • IN cells
  • Induced neuronal cells
  • Lysosomal storage diseases
  • Polyglutamine diseases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology

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    Kano, S., Yuan, M., Cardarelli, R. A., Maegawa, G., Higurashi, N., Gaval-Cruz, M., Wilson, A. M., Tristan, C., Kondo, M. A., Chen, Y., Koga, M., Obie, C., Ishizuka, K., Seshadri, S., Srivastava, R., Kato, T. A., Horiuchi, Y., Sedlak, T. W., Lee, Y., ... Kai, M. (2015). Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: Studies of lysosomal storage diseases and channelopathy. Current Molecular Medicine, 15(2), 138-145. https://doi.org/10.2174/1566524015666150303110300