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November 07, 2016

iPS cell model hints at physiological substances that can promote dopamine production by the brain

The Haruhisa Inoue lab uses iPS cells to study BH4 metabolism disorders

Parkinson's disease is marked by a significant deficiency in the brain's dopamine levels. According to CiRA neurologist Haruhisa Inoue, other brain diseases also show this deficiency. "BH4 metabolism disorders affect motor control like Parkinson's disease and are also caused by low levels of dopamine." BH4 metabolism disorders are the result of genetic mutations that compromise the synthesis of BH4, or tetrahydrobiopterin, through the production of defective enzymes. In a new publication published in Human Molecular Genetics, Inoue's lab reports a new physiological substance as a candidate treatment.

The researchers prepared iPS cells from patients with abnormalities in two specific enzymes and differentiated the cells to neurons. "Our patients have mutations for PTPS or DHPR," said Inoue. To study the molecular pathology of the neurons, they took a subset of iPS cells and corrected the mutation using CRISPR-Cas9 technology. As expected, in patients with the PTPS mutation, uncorrected iPS-derived neurons secreted less dopamine and expressed less BH4 than did those with the corrected form. On the other hand, while less dopamine was seen for cells taken from patients with the DHPR mutation, BH4 levels were unchanged. Inoue believes these results reflect the importance of identifying the cause of the disorder. "Findings like these demonstrate why not all patients respond well to the same drugs, because the molecular phenotypes are different," he explained.

Noting these differences, the research group investigated the effects of administering BH4 or sepiapterin, a precursor of BH4, in the PTPS patient cells, finding that while both increased dopamine levels, the sepiapterin effects were greater. Sepiapterin has also been reported to increase dopamine levels in neurons derived from Parkinson's disease iPS cells. Tazio Ishikawa, first author of the paper, believes these findings could lead to a different viewpoint of the diseases. "Although BH4 metabolism disorders and Parkinson's disease are categorized as different diseases, finding a common physiologically active substance for treatment based on common cellular phenotype will lead to disease repositioning of both diseases," he said.

Paper Details
  • Journal: Human Molecular Genetics

  • Title: Genetic and pharmacological correction of aberrant dopamine synthesis using patient iPSCs with BH4 metabolism disorders

  • Authors: Taizo Ishikawa1,2, Keiko Imamura1, Takayuki Kondo1, Yasushi Koshiba1,3, Satoshi Hara4, Hiroshi Ichinose4, Mahoko Furujo5, Masako Kinoshita6, Tomoko Oeda6, Jun Takahashi1, Ryosuke Takahashi3, Haruhisa Inoue1,*

  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
    2. Sumitomo Dainippon Pharma, 3-1-98 Kasugadenaka, Konohana-ku, Osaka 554-0022, Japan
    3. Department of Neurology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
    4. School of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
    5. Department of Pediatrics, Okayama Medical Center, National Hospital Organization, Okayama 701-1192, Japan
    6. Department of Neurology, Utano National Hospital, National Hospital Organization, Kyoto 616-8255, Japan
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