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Dysregulated COMT Expression in Fragile X Syndrome

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Abstract

Transcriptional and proteomics analyses in human fragile X syndrome (FXS) neurons identified markedly reduced expression of COMT, a key enzyme involved in the metabolism of catecholamines, including dopamine, epinephrine and norepinephrine. FXS is the most common genetic cause of intellectual disability and autism spectrum disorders. COMT encodes for catechol-o-methyltransferase and its association with neuropsychiatric disorders and cognitive function has been extensively studied. We observed a significantly reduced level of COMT in in FXS human neural progenitors and neurons, as well as hippocampal neurons from Fmr1 null mice. We show that deficits in COMT were associated with an altered response in an assay of dopaminergic activity in Fmr1 null mice. These findings demonstrate that loss of FMRP downregulates COMT expression and affects dopamine signaling in FXS, and supports the notion that targeting catecholamine metabolism may be useful in regulating certain neuropsychiatric aspects of FXS.

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Data Availability

The datasets used and/or analyzed during the current study are obtained from Utami et al., Biol Psych, 2020 (GEO (Gene Expression Omnibus) ID GSE117248 and ProteomeXchange consortium ID: PXD011630.

Abbreviations

FXS:

Fragile X syndrome

hPSC:

Human pluripotent stem cells

hESC:

Human embryonic stem cells

NPC:

Neural progenitor cells

SNPs:

Single-nucleotide polymorphism

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Acknowledgements

We thank Dr. Nikica Zaninovic (Weill Cornell Medical College) for the WCMC-37 FXS hESC line.

Funding

M.A.P. is the recipient of a BC Children’s Hospital Research Institute Investigator Grant Award (IGAP), and a Scholar Award from the Michael Smith Health Research BC. K.H.U. is the recipient of a FRAXA Fellowship.

Author information

Authors and Affiliations

  1. Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, 138648, Singapore

    Kagistia Hana Utami, Nur Amirah Binte Muhammed Yusof, Marta Garcia-Miralles & Mahmoud A. Pouladi

  2. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Kagistia Hana Utami & Sarah R. Langley

  3. Department of Molecular Embryology, Medical Faculty, Institute of Anatomy and Cell Biology, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany

    Marta Garcia-Miralles

  4. Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, 2200, Copenhagen, Denmark

    Niels Henning Skotte

  5. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Niels Henning Skotte

  6. Institute of Medical Biology, Agency for Science, Technology and Research, Singapore (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, 138648, Singapore

    Srikanth Nama

  7. Agency for Science, Technology and Research, Genome Institute of Singapore, 60 Biopolis Street, Genome, Singapore, 138672, Singapore

    Prabha Sampath

  8. Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore

    Prabha Sampath

  9. School of Biosciences, Cardiff University, Cardiff, CF10 3AX, UK

    Sarah R. Langley

  10. Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, Djavad Mowafaghian Centre for Brain Health, British Columbia Children’s Hospital Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada

    Mahmoud A. Pouladi

Authors
  1. Kagistia Hana Utami
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  2. Nur Amirah Binte Muhammed Yusof
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  4. Niels Henning Skotte
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  5. Srikanth Nama
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  6. Prabha Sampath
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  7. Sarah R. Langley
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  8. Mahmoud A. Pouladi
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Contributions

MAP and KHU designed the study, interpreted data and wrote the manuscript; NABMY, KHU, NS and MG-M performed the experimental work, analyzed and interpreted data. NABMY and KHU performed molecular analyses, NS performed proteomics experiments, MGM was responsible for animal work experiments and data interpretation. SRL supervised the study and interpreted RNAseq analysis. PS and SN designed, performed and analyzed the polysome-fractionation experiments. All the authors edited or commented the manuscript.

Corresponding author

Correspondence to Mahmoud A. Pouladi.

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The authors declare that they have no competing interests.

Ethical Approval

All animal procedures were in compliance with the Institutional Animal Care and Use Committee (IACUC) at the Biomedical Science Institute (A*STAR) and in accordance to their approved guidelines.

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Utami, K.H., Yusof, N.A.B.M., Garcia-Miralles, M. et al. Dysregulated COMT Expression in Fragile X Syndrome. Neuromol Med 25, 644–649 (2023). https://doi.org/10.1007/s12017-023-08754-1

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  • DOI: https://doi.org/10.1007/s12017-023-08754-1

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