Adeno-associated virus-mediated rescue of the cognitive defects in a mouse model for Angelman syndrome.
Adeno-associated virus-mediated rescue of the cognitive defects in a mouse model for Angelman syndrome.
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DOI：
10.1371/journal.pone.0027221
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Weeber EJ
中科院分区：
文献类型：
--
作者：
Daily JL;Nash K;Jinwal U;Golde T;Rogers J;Peters MM;Burdine RD;Dickey C;Banko JL;Weeber EJ
天使综合症（AS）是一种遗传性疾病，大约每15000个新生儿中就有1个发生，其特征是严重的智力迟钝、癫痫、说话困难和共济失调。研究发现，导致AS的基因是UBE3A，它编码一种泛素连接酶E6-AP。该基因的一个独特特征是它以神经元特异性的方式经历母体印记。在大多数AS病例中，母亲遗传的UBE3A基因存在突变或缺失，尽管其他病例是单亲二体或母亲基因错甲基化的结果。虽然大多数以严重智力迟钝为特征的人类疾病涉及大脑结构异常，但与AS无关的大体解剖改变。然而，我们已经确定，在母系UBE3A缺失AS小鼠模型中可以看到异常的钙/钙调素依赖性蛋白激酶II （CaMKII）调控，并负责主要表型。具体来说，在自磷酸化位点Thr286和Thr305/306处αCaMKII磷酸化增加，导致CaMKII活性整体下降。CaMKII直到出生后才产生，这表明与AS相关的缺陷不是发育异常的结果。目前的研究重点是探索通过使用腺相关病毒（AAV）载体增加神经元UBE3A表达来挽救成年AS小鼠模型的学习和记忆缺陷的潜力。这些研究表明，使用外源性载体增加大脑中E6-AP的水平可以改善与AS相关的认知缺陷。具体来说，与对照组相比，治疗后的AS小鼠的联想学习缺陷得到了改善，这表明治疗干预可能适用于老年AS患者。
Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. However, we have determined that abnormal calcium/calmodulin-dependent protein kinase II (CaMKII) regulation is seen in the maternal UBE3A deletion AS mouse model and is responsible for the major phenotypes. Specifically, there is an increased αCaMKII phosphorylation at the autophosphorylation sites Thr286 and Thr305/306, resulting in an overall decrease in CaMKII activity. CaMKII is not produced until after birth, indicating that the deficits associated with AS are not the result of developmental abnormalities. The present studies are focused on exploring the potential to rescue the learning and memory deficits in the adult AS mouse model through the use of an adeno-associated virus (AAV) vector to increase neuronal UBE3A expression. These studies show that increasing the levels of E6-AP in the brain using an exogenous vector can improve the cognitive deficits associated with AS. Specifically, the associative learning deficit was ameliorated in the treated AS mice compared to the control AS mice, indicating that therapeutic intervention may be possible in older AS patients.
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DOI：
10.1016/s0169-328x(99)00131-x
发表时间：
1999-06-18
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Bayer, KU;Löhler, J;Harbers, K
通讯作者：
Harbers, K
DOI：
10.1002/ajmg.1320320235
发表时间：
1989-02-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
KNOLL, JHM;NICHOLLS, RD;LATT, SA
通讯作者：
LATT, SA
影响因子：
4.8
作者：
Kumar, S;Talis, AL;Howley, PM
通讯作者：
Howley, PM
DOI：
10.1073/pnas.96.16.9258
发表时间：
1999-08-03
影响因子：
11.1
作者：
Gabriel, JM;Merchant, M;Nicholls, RD
通讯作者：
Nicholls, RD
DOI：
10.1089/cap.2006.16.525
发表时间：
2006-10-01
影响因子：
1.9
作者：
Berry-Kravis, Elizabeth;Krause, Sue Ellen;Hagerman, Randi
通讯作者：
Hagerman, Randi