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Association of protein distribution and gene expression revealed by positron emission tomography and postmortem gene expression in the dopaminergic system of the human brain

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Abstract

Purpose

The topological distribution of dopamine-related proteins is determined by gene transcription and subsequent regulations. Recent research strategies integrating positron emission tomography with a transcriptome atlas have opened new opportunities to understand the influence of regulation after transcription on protein distribution. Previous studies have reported that messenger (m)-RNA expression levels spatially correlate with the density maps of serotonin receptors but not with those of transporters. This discrepancy may be due to differences in regulation after transcription between presynaptic and postsynaptic proteins, which have not been studied in the dopaminergic system. Here, we focused on dopamine D1 and D2/D3 receptors and dopamine transporters and investigated their region-wise relationship between mRNA expression and protein distribution.

Methods

We examined the region-wise correlation between regional binding potentials of the target region relative to that of non-displaceable tissue (BPND) values of 11C-SCH-23390 and mRNA expression levels of dopamine D1 receptors (D1R); regional BPND values of 11C-FLB-457 and mRNA expression levels of dopamine D2/D3 receptors (D2/D3R); and regional total distribution volume (VT) values of 18F-FE-PE2I and mRNA expression levels of dopamine transporters (DAT) using Spearman’s rank correlation.

Results

We found significant positive correlations between regional BPND values of 11C-SCH-23390 and the mRNA expression levels of D1R (r = 0.769, p = 0.0021). Similar to D1R, regional BPND values of 11C-FLB-457 positively correlated with the mRNA expression levels of D2R (r = 0.809, p = 0.0151) but not with those of D3R (r = 0.413, p = 0.3095). In contrast to D1R and D2R, no significant correlation between VT values of 18F-FE-PE2I and mRNA expression levels of DAT was observed (r = -0.5934, p = 0.140).

Conclusion

We found a region-wise correlation between the mRNA expression levels of dopamine D1 and D2 receptors and their respective protein distributions. However, we found no region-wise correlation between the mRNA expression levels of dopamine transporters and their protein distributions, indicating different regulatory mechanisms for the localization of pre- and postsynaptic proteins. These results provide a broader understanding of the application of the transcriptome atlas to neuroimaging studies of the dopaminergic nervous system.

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Data availability

The data that support the findings of this study are available from the corresponding author on reasonable request. Sharing and reuse of data require the expressed written permission of the authors, as well as clearance from the Institutional Review Boards.

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Acknowledgements

The authors thank radiation technologists, clinical coordinators and the members of the Brain Disorder Translational Team for their support with the positron emission tomography scans; and the staff of the Department of Radiopharmaceuticals Development for their radioligand synthesis and metabolite analysis.

Funding

This study was supported by a Grant-in-Aid for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS; JP19dm0207072), the Strategic International Brain Science Research Promotion Program (Brain/MINDS Beyond; JP19dm0307105), and JST Grant Number JPMJMS2024, and AMED Grant Number 20356533 to Makoto Higuchi. It was also supported by JSPS KAKENHI 20K07935, MHLW KAKENHI 20GC1018, 22GC1004 to Keisuke Takahata, and JSPS KAKENHI 22K15770 to Yasuharu Yamamoto. No potential conflicts of interest relevant to this article exist.

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Authors and Affiliations

  1. Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage, Chiba, 263-8555, Japan

    Yasuharu Yamamoto, Keisuke Takahata, Manabu Kubota, Sho Moriguchi, Chie Seki, Hironobu Endo, Kiwamu Matsuoka, Kenji Tagai, Yasuyuki Kimura, Shin Kurose & Makoto Higuchi

  2. Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan

    Yasuharu Yamamoto, Hiroyoshi Takeuchi & Masaru Mimura

  3. Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo-Ku, Kyoto, 606-8507, Japan

    Manabu Kubota

  4. Department of Psychiatry, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi, Sumida-Ku, Tokyo, 130-8575, Japan

    Takeshi Sasaki

  5. Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi, 474-8511, Japan

    Yasuyuki Kimura

  6. Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage, Chiba, Chiba, 263-8555, Japan

    Kazunori Kawamura & Ming-Rong Zhang

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  1. Yasuharu Yamamoto
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  2. Keisuke Takahata
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  3. Manabu Kubota
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  4. Hiroyoshi Takeuchi
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  16. Makoto Higuchi
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Contributions

All authors contributed to the study conception and design. Yasuharu Yamamoto, Keisuke Takahata, Manabu Kubota, Hiroyoshi Takeuchi, Sho Moriguchi, Takeshi Sasaki, Chie Seki, Hironobu Endo, Kiwamu Matsuoka, Kenji Tagai, Yasuyuki Kimura, Shin Kurose, Masaru Mimura and Makoto Higuchi: data collection and analysis. Kazunori Kawamura and Ming-Rong Zhang: Radioligand synthesis. The first draft of the manuscript was written by Yasuharu Yamamoto and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Keisuke Takahata.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of the National Institutes for Quantum Science and Technology, Chiba, Japan.

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Yamamoto, Y., Takahata, K., Kubota, M. et al. Association of protein distribution and gene expression revealed by positron emission tomography and postmortem gene expression in the dopaminergic system of the human brain. Eur J Nucl Med Mol Imaging 50, 3928–3936 (2023). https://doi.org/10.1007/s00259-023-06390-2

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