An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of Phelan-McDermid syndrome.
An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of Phelan-McDermid syndrome.
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DOI：
10.1038/s41380-022-01904-0
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发表时间：
2023-03
影响因子：
11
通讯作者：
Penzes, Peter
中科院分区：
文献类型：
--
作者：
Burgdorf, Jeffrey S.;Yoon, Sehyoun;Dos Santos, Marc;Lammert, Catherine R.;Moskal, Joseph R.;Penzes, Peter
我们开发了一种 IGFBP2 模拟肽片段 JB2，并表明它可以促进培养神经元和小鼠的基础突触结构和功能可塑性。我们证明JB2直接与树突和突触结合，其生物活性涉及NMDA受体激活、基因转录和翻译以及IGF2受体。它不依赖于 IGF1 受体。在神经元中，JB2 诱导膜磷酸化蛋白质组的广泛重塑。突触和细胞骨架调节、自闭症谱系障碍 (ASD) 危险因素和 Shank3 相关蛋白网络在磷酸化和去磷酸化蛋白中显着富集。染色体 22q13.3 上 SHANK3 基因的单倍体不足通常会导致费兰-麦克德米德综合症 (PMS)，这是一种基因定义的自闭症形式，在运动行为、感觉处理、语言和认知功能方面存在严重缺陷。我们在 Shank3 杂合小鼠中鉴定出多种与疾病相关的表型，并表明 JB2 可以挽救突触功能和可塑性、学习和记忆、超声发声和运动功能方面的缺陷；它还使神经元兴奋性和癫痫易感性正常化。值得注意的是，JB2 挽救了听觉诱发反应潜伏期、α 峰值频率和稳态脑电图反应方面的缺陷，这些指标对人类受试者具有直接转化价值。这些数据表明，JB2 是一种有效的神经可塑性调节剂，具有治疗经前综合症和自闭症谱系障碍的潜力。
We developed an IGFBP2-mimetic peptide fragment, JB2, and showed that it promotes basal synaptic structural and functional plasticity in cultured neurons and mice. We demonstrate that JB2 directly binds to dendrites and synapses, and its biological activity involves NMDA receptor activation, gene transcription and translation, and IGF2 receptors. It is not IGF1 receptor-dependent. In neurons, JB2 induced extensive remodeling of the membrane phosphoproteome. Synapse and cytoskeletal regulation, autism spectrum disorder (ASD) risk factors, and a Shank3-associated protein network were significantly enriched among phosphorylated and dephosphorylated proteins. Haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 often causes Phelan-McDermid Syndrome (PMS), a genetically defined form of autism with profound deficits in motor behavior, sensory processing, language, and cognitive function. We identified multiple disease-relevant phenotypes in a Shank3 heterozygous mouse and showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalizations, and motor function; it also normalized neuronal excitability and seizure susceptibility. Notably, JB2 rescued deficits in the auditory evoked response latency, alpha peak frequency, and steady-state electroencephalography response, measures with direct translational value to human subjects. These data demonstrate that JB2 is a potent modulator of neuroplasticity with therapeutic potential for the treatment of PMS and ASD.
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影响因子：
4.9
作者：
Kolevzon A;Angarita B;Bush L;Wang AT;Frank Y;Yang A;Rapaport R;Saland J;Srivastava S;Farrell C;Edelmann LJ;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
1.9
作者：
Harony-Nicolas H;De Rubeis S;Kolevzon A;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
影响因子：
--
作者：
Yoon S;Penzes P
通讯作者：
Penzes P
影响因子：
6.2
作者：
Bozdagi O;Tavassoli T;Buxbaum JD
通讯作者：
Buxbaum JD