Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer's disease.
Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer's disease.
复制标题
异常的 DJ-1 表达是结节性硬化症和阿尔茨海默病树突中 L 型钙通道活性低下的基础。
DOI：
10.1073/pnas.2301534120
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发表时间：
2023
影响因子：
11.1
通讯作者：
Craf
中科院分区：
文献类型：
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作者：
Niere,Farr;Uneri,Ayse;McArdle,ColinJ;Deng,Zhiyong;Egido-Betancourt,HaileyX;Cacheaux,LuisaP;Namjoshi,SanjeevV;Taylor,WilliamC;Wang,Xin;Barth,SamuelH;Reynoldson,Cameron;Penaranda,Juan;Stierer,MichaelP;Heaney,ChelcieF;Craf
l型电压门控钙（Ca2+）通道（L-VGCC）功能障碍与几种神经和精神疾病有关。作为一种流行的治疗靶点，目前尚不清楚在神经退行性疾病中导致L-VGCC破坏的分子机制是否保守。重要的是，L-VGCC整合突触信号以促进过多的细胞机制；然而，调节L-VGCC通道密度和亚细胞区隔化的机制尚未得到充分研究。本文中，我们报告了在哺乳动物雷帕霉素靶蛋白复合物1 （mTORC1）信号传导过度活跃的疾病模型（或mtor病变）中，树突状L-VGCC活性缺陷与rna结合蛋白（RBP）帕金森病相关脱糖酶（DJ-1）表达增加相关。DJ-1结合编码α和辅助Ca2+通道亚基CaV1.2和α2δ2的mRNA，并抑制它们的mRNA翻译，仅在疾病状态下，特别是结节性硬化症（TSC）和阿尔茨海默病（AD）的临床前模型。与此一致的是，在AD和TSC小鼠模型中，dj -1介导的树突中CaV1.2/α2δ2蛋白合成的抑制被夸大，导致树突L-VGCC钙活性不足。在TSC和AD的树突中发现dj -1调节的L-VGCC活性，为临床病理提供了独特的信号通路。
L-type voltage-gated calcium (Ca2+) channels (L-VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown whether molecular mechanisms leading to disrupted L-VGCC across neurodegenerative disorders are conserved. Importantly, L-VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L-VGCC channel density and subcellular compartmentalization are understudied. Herein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L-VGCC activity are associated with increased expression of the RNA-binding protein (RBP) Parkinsonism-associated deglycase (DJ-1). DJ-1 binds the mRNA coding for the alpha and auxiliary Ca2+channel subunits CaV1.2 and α2δ2, and represses their mRNA translation, only in the disease states, specifically preclinical models of tuberous sclerosis complex (TSC) and Alzheimer’s disease (AD). In agreement, DJ-1-mediated repression of CaV1.2/α2δ2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L-VGCC calcium activity. Finding of DJ-1-regulated L-VGCC activity in dendrites in TSC and AD provides a unique signaling pathway that can be targeted in clinical mTORopathies.