gaba能神经元功能障碍是脊髓小脑共济失调果蝇模型震颤的基础。

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Animesh Banerjee, Moumita Chatterjee, Kah Junn Tan, Shermaine Tay, Kaibo Duan, Anand Kumar Andiappan, Shanshan Wu Howland, Yoshinori Aso, Sherry Shiying Aw
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引用次数: 0

摘要

震颤是一种常见的运动障碍,与几种神经退行性疾病有关,但其机制尚不清楚。使用机器学习方法FLLIT,我们之前在果蝇脊髓小脑性共济失调3 (SCA3)模型中表征了步态和震颤特征,并发现它们与人类SCA3相似。在这里,我们对导致震颤的神经元群进行了功能筛选,发现腹侧神经索(VNC)特定神经元群的功能障碍是震颤的必要和充分条件。ATXN3突变体在这些神经元中的表达或基因低激活导致震颤,表明它们在成人运动控制中起重要作用。RNAseq和功能实验表明,引起震颤的是gaba能神经元的功能障碍,而不是其他被测试的神经递质群体。最后,我们确定了成人VNC中大约30个主要gaba能神经元的一小部分,这些神经元对于平稳行走至关重要。本研究表明,SCA3果蝇的震颤是由gaba能功能障碍引起的,FLLIT可用于解剖运动控制机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
GABAergic neuronal dysfunction underlies tremor in a Drosophila model of Spinocerebellar ataxia 3.

Tremor is a common movement disorder associated with several neurodegenerative diseases, yet its mechanisms are not well understood. Using a machine learning method, FLLIT, we previously characterised gait and tremor signatures in the Drosophila model for Spinocerebellar ataxia 3 (SCA3), and found them to be analogous to human SCA3. Here, we carried out a functional screen for neuronal populations that underlie tremor, and found that dysfunction of a specific population of neurons in the ventral nerve cord (VNC) is necessary and sufficient for tremor. Adult-onset expression of mutant ATXN3 in or genetic hypo-activation of these neurons leads to tremor, indicating their important role in adult motor control. RNAseq and functional experiments showed that dysfunction of GABAergic neurons, and not other neurotransmitter populations tested, causes tremor. Finally, we identified a small subset of approximately 30 predominantly GABAergic neurons within the adult VNC that are essential for smooth walking. This study demonstrates that tremor in SCA3 flies arises from GABAergic dysfunction, and that FLLIT can be used to dissect motor control mechanisms.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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