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FAME4-associating YEATS2 knockdown impairs dopaminergic synaptic integrity and leads to seizure-like behaviours in Drosophila melanogaster

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2024

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Lo Piccolo, Luca
Yeewa, Ranchana
Pohsa, Sureena
Yamsri, Titaree
Phetcharaburanin, Jutarop
Suksawat, Manida
Kulthawatsiri, Thanaporn
Shotelersuk, Vorasuk
Jantrapirom, Salinee

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Progress in Neurobiology. Elsevier. 2024, 233, 102558. ISSN 0301-0082. eISSN 1873-5118. Available under: doi: 10.1016/j.pneurobio.2023.102558

Zusammenfassung

Familial adult myoclonus epilepsy (FAME) is a neurological disorder caused by a TTTTA/TTTCA intronic repeat expansion. FAME4 is one of the six types of FAME that results from the repeat expansion in the first intron of the gene YEATS2. Although the RNA toxicity is believed to be the primary mechanism underlying FAME, the role of genes where repeat expansions reside is still unclear, particularly in the case of YEATS2 in neurons. This study used Drosophila to explore the effects of reducing YEATS2 expression. Two pan-neuronally driven dsDNA were used for knockdown of Drosophila YEATS2 (dYEATS2), and the resulting molecular and behavioural outcomes were evaluated. Drosophila with reduced dYEATS2 expression exhibited decreased tolerance to acute stress, disturbed locomotion, abnormal social behaviour, and decreased motivated activity. Additionally, reducing dYEATS2 expression negatively affected tyrosine hydroxylase (TH) gene expression, resulting in decreased dopamine biosynthesis. Remarkably, seizure-like behaviours induced by knocking down dYEATS2 were rescued by the administration of L-DOPA. This study reveals a novel role of YEATS2 in neurons in regulating acute stress responses, locomotion, and complex behaviours, and suggests that haploinsufficiency of YEATS2 may play a role in FAME4.

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570 Biowissenschaften, Biologie

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ISO 690LO PICCOLO, Luca, Ranchana YEEWA, Sureena POHSA, Titaree YAMSRI, Daniel S. CALOVI, Jutarop PHETCHARABURANIN, Manida SUKSAWAT, Thanaporn KULTHAWATSIRI, Vorasuk SHOTELERSUK, Salinee JANTRAPIROM, 2024. FAME4-associating YEATS2 knockdown impairs dopaminergic synaptic integrity and leads to seizure-like behaviours in Drosophila melanogaster. In: Progress in Neurobiology. Elsevier. 2024, 233, 102558. ISSN 0301-0082. eISSN 1873-5118. Available under: doi: 10.1016/j.pneurobio.2023.102558
BibTex
@article{LoPiccolo2024FAME4-69421,
  year={2024},
  doi={10.1016/j.pneurobio.2023.102558},
  title={FAME4-associating YEATS2 knockdown impairs dopaminergic synaptic integrity and leads to seizure-like behaviours in Drosophila melanogaster},
  volume={233},
  issn={0301-0082},
  journal={Progress in Neurobiology},
  author={Lo Piccolo, Luca and Yeewa, Ranchana and Pohsa, Sureena and Yamsri, Titaree and Calovi, Daniel S. and Phetcharaburanin, Jutarop and Suksawat, Manida and Kulthawatsiri, Thanaporn and Shotelersuk, Vorasuk and Jantrapirom, Salinee},
  note={Article Number: 102558}
}
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