Dopamine D2 long receptors are critical for caveolae-mediated α-synuclein uptake in cultured dopaminergic neurons

Ichiro Kawahata, Tomoki Sekimori, Haoyang Wang, Yanyan Wang, Toshikuni Sasaoka, Luc Bousset, Ronald Melki, Tomohiro Mizobata, Yasushi Kawata, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

α-synuclein accumulation into dopaminergic neurons is a pathological hallmark of Parkin-son’s disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3) is critical for α-synuclein uptake and propagation to accumulate in dopaminergic neurons. FABP3 is abundant in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D2L). Here, we investigated the importance of dopamine D2L receptors in the uptake of α-synuclein monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D2L−/−, dopamine D2 receptor null (D2 null), FABP3−/−, and wild type C57BL6 mice, and analyzed the uptake ability of fluorescence-conjugated α-synuclein monomers and fibrils. We found that D2L receptors are co-localized with FABP3. Immunocytochemistry revealed that TH+ D2L−/− or D2 null neurons do not take up α-synuclein monomers. The deletion of α-synuclein C-terminus completely abolished the uptake to dopamine neurons. Likewise, dynasore, a dynamin inhibitor, and caveolin-1 knockdown also abolished the uptake. D2L and FABP3 were also critical for α-synuclein fibrils uptake. D2L and accumulated α-synuclein fibrils were well co-localized. These data indicate that dopamine D2L with a caveola structure coupled with FABP3 is critical for α-synuclein uptake by dopaminergic neurons, suggesting a novel pathogenic mechanism of synucleinopathies, including Parkinson’s disease.

Original languageEnglish
Article number49
Pages (from-to)1-14
Number of pages14
JournalBiomedicines
Volume9
Issue number1
DOIs
Publication statusPublished - 2021

Keywords

  • Dopamine D receptor
  • Dopaminergic neurons
  • Fatty acid-binding protein 3 (FABP3)
  • Parkinson’s disease
  • Synucleinopathy
  • α-synuclein

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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