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JNK signaling activation in the Ube3a maternal deficient mouse model: Its specific inhibition prevents post-synaptic protein-enriched fraction alterations and cognitive deficits in Angelman Syndrome model.

Ube3a 母体缺陷小鼠模型中的 JNK 信号激活: 其特异性抑制可防止 Angelman 综合征模型中的突触后蛋白富集部分改变和认知缺陷。

  • 影响因子:5.36
  • DOI:10.1016/j.nbd.2020.104812
  • 作者列表:"Musi CA","Agrò G","Buccarello L","Camuso S","Borsello T
  • 发表时间:2020-02-19
Abstract

:Deficiency of the E3 ubiquitin ligase UBE3A leads to the neurodevelopmental disorder Angelman syndrome (AS), while higher levels are linked to autism spectrum disorder. The mechanisms underlying the downstream effects of UBE3A loss or gain of function in these disorders are still not well understood, and treatments are still lacking. Here, using the Ube3a maternal loss (Ube3am-/p+) mouse model, we report an important JNK signaling activation in the hippocampus, cortex and cerebellum correlating with the onset of behavioral defects and biochemical marker alterations in the post-synaptic element, suggesting important spine pathology. JNK activation occurs at 7 and persists up till 23 weeks in Ube3am-/p+ mice in two different cellular compartments: the nucleus and the post-synaptic protein-enriched fraction. To study JNK's role in Ube3am-/p+ pathology we treated mice with the specific JNK inhibitor peptide, D-JNKI1, from 7 to 23 weeks of age. Preventing JNK action in vivo restores the post-synaptic protein-enriched fraction defects and the cognitive impairment in these mice. Our results imply a critical role of UBE3A-JNK signaling in the pathogenesis of UBE3A-related disorders. In particular, it was clear that JNK is a key player in regulating AS synaptic alterations and the correlated cognitive impairments, in fact, its specific inhibition tackles Ube3am-/p+ pathology. This study sheds new light on the neuronal functions of UBE3A and offers new prospects for understanding the pathogenesis of UBE3A-related disorders.

摘要

: E3 泛素连接酶 UBE3A 的缺乏导致神经发育障碍 Angelman 综合征 (AS),而较高水平与自闭症谱系障碍有关。这些疾病中 UBE3A 丧失或功能获得的下游效应的潜在机制仍不清楚,治疗仍缺乏。在这里,使用 Ube3a 母体缺失 (Ube3am-/p +) 小鼠模型,我们报道了海马中重要的 JNK 信号激活, 皮层和小脑与行为缺陷的发生和突触后元件的生化标志物改变有关,提示重要的脊柱病理。JNK 激活发生在 7 时,在 Ube3am-/p + 小鼠中持续至 23 周,位于两个不同的细胞区室: 细胞核和突触后蛋白富集部分。为了研究 JNK 在 Ube3am-/p + 病理中的作用,我们用特定的 JNK 抑制剂肽 D-JNKI1 对 7 ~ 23 周龄小鼠进行治疗。体内预防 JNK 作用可恢复这些小鼠突触后蛋白富集部分缺陷和认知障碍。我们的结果暗示 UBE3A-JNK 信号在 UBE3A-related 疾病发病机制中的关键作用。特别是,很明显,JNK 是调节 AS 突触改变和相关认知障碍的关键因子,事实上,它的特异性抑制处理 Ube3am-/p + 病理学。本研究对 UBE3A 的神经元功能有了新的认识,为理解 UBE3A-related 疾病的发病机制提供了新的前景。

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发表时间:2020-01-19
来源期刊:Neuroscience letters
DOI:10.1016/j.neulet.2019.134696
作者列表:["Battaglini L","Contemori G","Penzo S","Maniglia M"]

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影响因子:5.13
发表时间:2020-01-16
DOI:10.1088/1741-2552/ab6cb6
作者列表:["Pelot NA","Grill WM"]

METHODS:OBJECTIVE:There is growing interest in treating diseases by electrical stimulation and block of peripheral autonomic nerves, but a paucity of studies on excitation and block of small diameter autonomic axons. We conducted in vivo quantification of the strength-duration properties, activity-dependent slowing (ADS), and responses to kilohertz frequency (KHF) signals for the rat vagus nerve (VN). APPROACH:We conducted acute in vivo experiments in urethane-anesthetised rats. We placed two cuff electrodes on the left cervical VN and one cuff electrode on the anterior subdiaphragmatic VN. The rostral cervical cuff was used to deliver pulses to quantify recruitment and ADS. The caudal cervical cuff was used to deliver KHF signals. The subdiaphragmatic cuff was used to record compound action potentials (CAPs). MAIN RESULTS:We quantified the input-output recruitment and strength-duration curves. Fits to the data using standard strength-duration equations were qualitatively similar, but the resulting chronaxie and rheobase estimates varied substantially. We measured larger thresholds for the slowest fibres (0.5 to 1 m/s), especially at shorter pulse widths. Using a novel cross-correlation CAP-based analysis, we measured ADS of ~2.3% after 3 min of 2 Hz stimulation, which is comparable to ADS reported for sympathetic efferents in somatic nerves, but much smaller than ADS in cutaneous nociceptors. We found greater ADS with higher stimulation frequency and non-monotonic changes in CV in select cases. We found monotonically increasing block thresholds across frequencies from 10 to 80 kHz for both fast and slow fibres. Further, following 25 s of KHF signal, neural conduction could require tens of seconds to recover. SIGNIFICANCE:The quantification of mammalian autonomic nerve responses to conventional and KHF signals provides essential information for development of peripheral nerve stimulation therapies and for understanding their mechanisms of action.

影响因子:2.48
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DOI:10.1016/j.yebeh.2019.106644
作者列表:["Liu A","Friedman D","Barron DS","Wang X","Thesen T","Dugan P"]

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