敲除 FAME4-associating YEATS2 会损害黑腹果蝇多巴胺能突触的完整性并导致癫痫样行为

IF 6.7 2区 医学 Q1 NEUROSCIENCES
Luca Lo Piccolo , Ranchana Yeewa , Sureena Pohsa , Titaree Yamsri , Daniel Calovi , Jutarop Phetcharaburanin , Manida Suksawat , Thanaporn Kulthawatsiri , Vorasuk Shotelersuk , Salinee Jantrapirom
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引用次数: 0

摘要

家族性成人肌阵挛癫痫(FAME)是一种由 TTTTA/TTTCA 内含子重复扩增引起的神经系统疾病。FAME4 是由基因 YEATS2 第一个内含子的重复扩增导致的六种 FAME 类型之一。虽然 RNA 毒性被认为是 FAME 的主要机制,但重复扩增所在基因的作用仍不清楚,尤其是 YEATS2 在神经元中的作用。本研究利用果蝇来探索减少 YEATS2 表达的影响。研究使用了两种泛神经元驱动的dsDNA来敲除果蝇YEATS2(dYEATS2),并评估了由此产生的分子和行为结果。dYEATS2 表达减少的果蝇表现出对急性应激的耐受性降低、运动紊乱、社交行为异常和动机活动减少。此外,减少 dYEATS2 的表达还会对酪氨酸羟化酶(TH)基因的表达产生负面影响,导致多巴胺的生物合成减少。值得注意的是,敲除 dYEATS2 所诱发的癫痫样行为可通过服用 L-DOPA 得到挽救。这项研究揭示了YEATS2在神经元中调节急性应激反应、运动和复杂行为的新作用,并表明YEATS2的单倍体缺陷可能在FAME4中发挥作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
FAME4-associating YEATS2 knockdown impairs dopaminergic synaptic integrity and leads to seizure-like behaviours in Drosophila melanogaster

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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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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