Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel.,Science Translational Medicine

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Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel.
Science Translational Medicine ( IF 15.8 ) Pub Date : 2017-12-13 , DOI: 10.1126/scitranslmed.aah4985
George K E Umanah _{1,

2} , Marco Pignatelli ₃ , Xiling Yin _{1,

2} , Rong Chen _{1,

2} , Joshua Crawford ₄ , Stewart Neifert _{1,

2} , Leslie Scarffe _{1,

2,

5} , Adam A Behensky _{1,

2} , Noah Guiberson _{1,

2} , Melissa Chang ₅ , Erica Ma ₆ , Jin Wan Kim ₇ , Cibele C Castro _{1,

8} , Xiaobo Mao _{1,

2} , Li Chen _{1,

2} , Shaida A Andrabi _{1,

2} , Mikhail V Pletnikov ₄ , Ann E Pulver ₄ , Dimitrios Avramopoulos _{4,

9} , Antonello Bonci _{3,

4} , David Valle _{9,

10} , Ted M Dawson _{1,

2,

5,

11} , Valina L Dawson _{1,

2,

5,

12}

Affiliation

Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
School of Public Health, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Biochemistry, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of ATAD1, the gene encoding Thorase, in a cohort of patients with schizophrenia and healthy controls revealed rare Thorase variants. These variants caused defects in glutamatergic signaling by impairing AMPAR internalization and recycling in mouse primary cortical neurons. This contributed to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Heterozygous Thorase-deficient mice engineered to express these Thorase variants showed altered synaptic transmission and several behavioral deficits compared to heterozygous Thorase-deficient mice expressing wild-type Thorase. These behavioral impairments were rescued by the competitive AMPAR antagonist Perampanel, a U.S. Food and Drug Administration–approved drug. These findings suggest that Perampanel may be useful for treating disorders involving compromised AMPAR-mediated glutamatergic neurotransmission.

中文翻译：

胸苷变体与谷氨酰胺能神经传递缺陷有关，可以被Perampanel挽救。

AAA +腺苷三磷酸酶（ATPase）酶通过调节表面α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的表达在控制突触可塑性中起关键作用。ATAD1外显子的双向测序在患有精神分裂症和健康对照的队列研究中，编码Thorase的基因揭示了罕见的Thorase变体。这些变体通过损害AMPAR内在化和小鼠原代皮层神经元的再循环而在谷氨酸能信号传导中引起缺陷。这有助于增加AMPAR亚基GluA2的表面表达并增强突触传递。与表达野生型Thorase的杂合Thorase缺陷小鼠相比，经工程改造以表达这些Thorase变体的杂合Thorase缺陷小鼠表现出改变的突触传递和一些行为缺陷。这些行为障碍已通过竞争性AMPAR拮抗剂Perampanel（美国食品和药物管理局批准的药物）得以挽救。

更新日期：2017-12-15

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