Neuronal knockdown of Cullin3 as a Drosophila model of autism spectrum disorder.
Neuronal knockdown of Cullin3 as a Drosophila model of autism spectrum disorder.
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DOI：
10.1038/s41598-024-51657-9
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发表时间：
2024-01-17
影响因子：
4.6
通讯作者：
Shirasu-Hiza M
中科院分区：
文献类型：
--
作者：
Tener SJ;Lin Z;Park SJ;Oraedu K;Ulgherait M;Van Beek E;Martínez-Muñiz A;Pantalia M;Gatto JA;Volpi J;Stavropoulos N;Ja WW;Canman JC;Shirasu-Hiza M
Cullin-3（Cul 3）是编码泛素连接酶的保守基因，其突变与自闭症谱系障碍（ASD）密切相关。在这里，我们的特点ASD相关的病理所造成的神经元特异性Cul 3敲低果蝇。我们证实，神经元Cul 3敲低导致睡眠时间短，与ASD中的睡眠障碍平行。由于睡眠缺陷和ASD与代谢失调有关，我们测试了神经元Cul 3基因敲除果蝇的饥饿反应;它们比对照组饥饿更快，甘油三酯水平更低，表明代谢稳态存在缺陷。ASD的特征还在于氧化应激的生物标志物增加;我们发现神经元Cul 3敲低增加了对高氧（一种外源性氧化应激）的敏感性。ASD的其他特征是社交互动和学习方面的缺陷。使用一个求爱抑制试验，测量社会互动和以前的求爱记忆，我们发现，神经元Cul 3敲低减少求爱和学习相比，控制。最后，我们发现神经元Cul 3的缺失改变了蘑菇体的解剖结构，蘑菇体是记忆和睡眠所需的大脑区域。总之，ASD相关的神经元Cul 3敲除果蝇的表型建立这些苍蝇作为遗传模型，以研究ASD病理学的分子和细胞机制，包括代谢和氧化应激失调和神经发育。
Mutations in Cullin-3 (Cul3), a conserved gene encoding a ubiquitin ligase, are strongly associated with autism spectrum disorder (ASD). Here, we characterize ASD-related pathologies caused by neuron-specific Cul3 knockdown in Drosophila. We confirmed that neuronal Cul3 knockdown causes short sleep, paralleling sleep disturbances in ASD. Because sleep defects and ASD are linked to metabolic dysregulation, we tested the starvation response of neuronal Cul3 knockdown flies; they starved faster and had lower triacylglyceride levels than controls, suggesting defects in metabolic homeostasis. ASD is also characterized by increased biomarkers of oxidative stress; we found that neuronal Cul3 knockdown increased sensitivity to hyperoxia, an exogenous oxidative stress. Additional hallmarks of ASD are deficits in social interactions and learning. Using a courtship suppression assay that measures social interactions and memory of prior courtship, we found that neuronal Cul3 knockdown reduced courtship and learning compared to controls. Finally, we found that neuronal Cul3 depletion alters the anatomy of the mushroom body, a brain region required for memory and sleep. Taken together, the ASD-related phenotypes of neuronal Cul3 knockdown flies establish these flies as a genetic model to study molecular and cellular mechanisms underlying ASD pathology, including metabolic and oxidative stress dysregulation and neurodevelopment.
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影响因子：
9.8
作者：
Hill VM;O'Connor RM;Sissoko GB;Irobunda IS;Leong S;Canman JC;Stavropoulos N;Shirasu-Hiza M
通讯作者：
Shirasu-Hiza M
影响因子：
64.5
作者：
Cheng, YZ;Endo, K;Davis, RL
通讯作者：
Davis, RL
影响因子：
48
作者：
Deshpande, Sonali A.;Carvalho, Gil B.;Amador, Ariadna;Phillips, Angela M.;Hoxha, Sany;Lizotte, Keith J.;Ja, William W.
通讯作者：
Ja, William W.
影响因子：
56.9
作者：
DEBELLE, JS;HEISENBERG, M
通讯作者：
HEISENBERG, M
影响因子：
3.7
作者：
De Angelis M;Piccolo M;Vannini L;Siragusa S;De Giacomo A;Serrazzanetti DI;Cristofori F;Guerzoni ME;Gobbetti M;Francavilla R
通讯作者：
Francavilla R