蛋白质稳态
蛋白酶体
FMR1型
脆性X综合征
过度活跃
海马结构
蛋白质降解
生物
神经科学
硼替佐米
泛素
细胞生物学
内科学
医学
遗传学
等位基因
基因
多发性骨髓瘤
作者
Susana R. Louros,Sang Soo Seo,Beatriz Maio,Cristina Martinez‐Gonzalez,Miguel A. Gonzalez‐Lozano,Melania Muscas,Nick C. Verity,Jimi Wills,Ka Wan Li,Matthew F. Nolan,Emily K. Osterweil
出处
期刊:Neuron
[Elsevier]
日期:2022-12-09
卷期号:111 (4): 508-525.e7
被引量:12
标识
DOI:10.1016/j.neuron.2022.11.012
摘要
In fragile X syndrome (FX), the leading monogenic cause of autism, excessive neuronal protein synthesis is a core pathophysiology; however, an overall increase in protein expression is not observed. Here, we tested whether excessive protein synthesis drives a compensatory rise in protein degradation that is protective for FX mouse model (Fmr1-/y) neurons. Surprisingly, although we find a significant increase in protein degradation through ubiquitin proteasome system (UPS), this contributes to pathological changes. Normalizing proteasome activity with bortezomib corrects excessive hippocampal protein synthesis and hyperactivation of neurons in the inferior colliculus (IC) in response to auditory stimulation. Moreover, systemic administration of bortezomib significantly reduces the incidence and severity of audiogenic seizures (AGS) in the Fmr1-/y mouse, as does genetic reduction of proteasome, specifically in the IC. Together, these results identify excessive activation of the UPS pathway in Fmr1-/y neurons as a contributor to multiple phenotypes that can be targeted for therapeutic intervention.
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