CIM6P/IGF-2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice.
CIM6P/IGF-2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice.
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DOI：
10.1002/aur.2418
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Alberini CM
中科院分区：
文献类型：
--
作者：
Cruz E;Descalzi G;Steinmetz A;Scharfman HE;Katzman A;Alberini CM
Angelman综合征（AS）是一种主要影响神经系统的遗传性疾病，其特征是发育迟缓、智力残疾、严重言语障碍以及运动和平衡问题（共济失调）。大多数受影响的儿童也有反复发作（癫痫）。没有现有的治疗方法能够全面治疗AS的缺陷;因此，迫切需要确定新的治疗方法。在这里，我们表明，胰岛素样生长因子2（IGF-2）和甘露糖-6-磷酸（M6 P），配体的两个独立的结合位点的阳离子非依赖性M6 P/IGF-2受体（CIM 6P/IGF-2 R），逆转大多数主要缺陷的AS模型小鼠。皮下注射IGF-2或M6 P在AS模型小鼠中恢复了认知障碍，如通过测量上下文和识别记忆、通过旋转棒和后肢紧握评估的运动缺陷以及通过Y-迷宫测量的工作记忆/灵活性所评估的。IGF-2还纠正大理石掩埋的缺陷，并显着衰减声学诱导的癫痫发作。一组观察性测试证实，两种配体都没有改变基本功能，包括身体特征、一般行为反应和感觉反射，这表明它们相对安全。我们的数据提供了强有力的临床前证据，靶向CIM 6P/IGF-2 R是开发AS新疗法的有前途的方法。神经发育障碍安格尔曼综合征（AS）尚无有效的治疗方法。在这项研究中，我们使用经验证的AS小鼠模型Ube 3am −/p+，表明全身给予阳离子非依赖性甘露糖-6-磷酸受体（也称为胰岛素样生长因子2受体（CIM 6P/IGF-2 R））的配体可逆转与AS相关的认知障碍，运动缺陷以及癫痫发作。因此，激活CIM 6P/IGF-2 R的配体可能是AS的新的潜在治疗靶点。
Angelman syndrome (AS), a genetic disorder that primarily affects the nervous system, is characterized by delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments. Here we show that insulin-like growth factor 2 (IGF-2) and mannose-6-phosphate (M6P), ligands of two independent binding sites of the cation-independent M6P/IGF-2 receptor (CIM6P/IGF-2R), reverse most major deficits of AS modeled in mice. Subcutaneous injection of IGF-2 or M6P in mice modeling AS restored cognitive impairments as assessed by measurements of contextual and recognition memories, motor deficits assessed by rotarod and hindlimb clasping, and working memory/flexibility measured by Y-maze. IGF-2 also corrected deficits in marble burying and significantly attenuated acoustically induced seizures. An observational battery of tests confirmed that neither ligand changed basic functions including physical characteristics, general behavioral responses, and sensory reflexes, indicating that they are relatively safe. Our data provide strong preclinical evidence that targeting CIM6P/IGF-2R is a promising approach for developing novel therapeutics for AS. There is no effective treatment for the neurodevelopmental disorder Angelman syndrome (AS). Using a validated AS mouse model, the Ube3am−/p+, in this study we show that systemic administration of ligands of the cation independent mannose-6-phosphate receptor, also known as insulin-like growth factor 2 receptor (CIM6P/IGF-2R) reverses cognitive impairment, motor deficits, as well as seizures associated with AS. Thus, ligands that activate the CIM6P/IGF-2R may represent novel, potential therapeutic targets for AS.
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影响因子：
15.9
作者：
Mabb, Angela M.;Judson, Matthew C.;Zylka, Mark J.;Philpot, Benjamin D.
通讯作者：
Philpot, Benjamin D.
影响因子：
4.7
作者：
Louros SR;Osterweil EK
通讯作者：
Osterweil EK
影响因子：
64.8
作者：
Huang, Hsien-Sung;Allen, John A.;Mabb, Angela M.;King, Ian F.;Miriyala, Jayalakshmi;Taylor-Blake, Bonnie;Sciaky, Noah;Dutton, J. Walter, Jr.;Lee, Hyeong-Min;Chen, Xin;Jin, Jian;Bridges, Arlene S.;Zylka, Mark J.;Roth, Bryan L.;Philpot, Benjamin D.
通讯作者：
Philpot, Benjamin D.
DOI：
10.2201/nonlin.003.01.002
发表时间：
2005-01-01
期刊：
Nonlinearity in Biology Toxicology and Medicine
影响因子：
--
作者：
Baldi, Elisabetta;Bucherelli, Corrado
通讯作者：
Bucherelli, Corrado
影响因子：
4.7
作者：
Ciarlone, Stephanie L.;Wang, Xinming;Weeber, Edwin J.
通讯作者：
Weeber, Edwin J.