Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders.
Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders.
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DOI：
10.1038/s41380-020-00997-9
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发表时间：
2021-09
影响因子：
11
通讯作者：
Bardoni B
中科院分区：
文献类型：
--
作者：
Delhaye S;Bardoni B
磷酸二酯酶（PDE）是参与cAMP和cGMP的稳态的酶。它们是蛋白质家族的成员，该家族包括具有不同底物特异性的11个亚家族。它们的主要功能是催化cAMP、cGMP或两者的水解。cAMP和cGMP是两种关键的第二信使，其调节广泛的细胞内过程和神经行为功能，包括记忆和认知。即使这些酶存在于所有组织中，我们也专注于那些在大脑中表达的PDE。我们考虑了受神经发育障碍影响的患者的遗传变异，动物模型的表型，以及PDE抑制剂的药理作用，PDE抑制剂是一类快速发展并越来越多地应用于脑部疾病的药物。总的来说，这些数据表明PDE调节剂治疗以学习和记忆障碍、与抑郁症相关的行为改变和社会交往缺陷为特征的神经发育疾病的潜力。事实上，治疗阿尔茨海默病、精神分裂症、抑郁症和自闭症谱系障碍的临床试验正在进行中。在最近的结果中，一些PDE抑制剂（PDE 2A，PDE 3，PDE 4/4D和PDE 10A）用于治疗神经发育疾病，包括自闭症谱系障碍和智力残疾，这是一个重大进展，因为没有特定的治疗方法可用于这些患病率很高的疾病。此外，为了突出几种PDE在正常和病理性神经发育中的作用，我们在这里集中于与CC 2D 1A基因相关的唐氏综合征、脆性X综合征、Rett综合征和智力残疾中cAMP和/或cGMP的失调。
Phosphodiesterases (PDEs) are enzymes involved in the homeostasis of both cAMP and cGMP. They are members of a family of proteins that includes 11 subfamilies with different substrate specificities. Their main function is to catalyze the hydrolysis of cAMP, cGMP, or both. cAMP and cGMP are two key second messengers that modulate a wide array of intracellular processes and neurobehavioral functions, including memory and cognition. Even if these enzymes are present in all tissues, we focused on those PDEs that are expressed in the brain. We took into consideration genetic variants in patients affected by neurodevelopmental disorders, phenotypes of animal models, and pharmacological effects of PDE inhibitors, a class of drugs in rapid evolution and increasing application to brain disorders. Collectively, these data indicate the potential of PDE modulators to treat neurodevelopmental diseases characterized by learning and memory impairment, alteration of behaviors associated with depression, and deficits in social interaction. Indeed, clinical trials are in progress to treat patients with Alzheimer’s disease, schizophrenia, depression, and autism spectrum disorders. Among the most recent results, the application of some PDE inhibitors (PDE2A, PDE3, PDE4/4D, and PDE10A) to treat neurodevelopmental diseases, including autism spectrum disorders and intellectual disability, is a significant advance, since no specific therapies are available for these disorders that have a large prevalence. In addition, to highlight the role of several PDEs in normal and pathological neurodevelopment, we focused here on the deregulation of cAMP and/or cGMP in Down Syndrome, Fragile X Syndrome, Rett Syndrome, and intellectual disability associated with the CC2D1A gene.
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影响因子：
6.2
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
影响因子：
7
作者：
Castagnola S;Cazareth J;Lebrigand K;Jarjat M;Magnone V;Delhaye S;Brau F;Bardoni B;Maurin T
通讯作者：
Maurin T
影响因子：
16.2
作者：
Boyken, Janina;Gronborg, Mads;Chua, John Jia En
通讯作者：
Chua, John Jia En
DOI：
10.1073/pnas.1834280100
发表时间：
2003-09-02
影响因子：
11.1
作者：
Bourtchouladze, R;Lidge, R;Tully, T
通讯作者：
Tully, T
影响因子：
5.3
作者：
Choi, Catherine H.;Schoenfeld, Brian P.;McBride, Sean M. J.
通讯作者：
McBride, Sean M. J.