Neurocalcin Delta Knockout Impairs Adult Neurogenesis Whereas Half Reduction Is Not Pathological
Neurocalcin Delta Knockout Impairs Adult Neurogenesis Whereas Half Reduction Is Not Pathological
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DOI：
10.3389/fnmol.2019.00019
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发表时间：
2019-02-12
影响因子：
4.8
通讯作者：
Wirth, Brunhilde
中科院分区：
文献类型：
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作者：
Upadhyay, Aaradhita;Hosseinibarkooie, Seyyedmohsen;Wirth, Brunhilde
神经钙蛋白δ（NCALD）是一种脑富集神经元钙传感器，其减少可以预防脊髓性肌萎缩（SMA）。然而，NCALD的生理功能和减少NCALD的意义仍然是难以捉摸的。在这里，我们分析了纯合子（Ncald（KO/KO））和杂合子（Ncald（KO/WT））小鼠中普遍存在的Ncald敲除，以揭示NCALD在大脑中的生理作用，并研究50% NCALD减少是否是SMA治疗的安全选择。我们发现Ncald（KO/KO）而非Ncald（KO/WT）小鼠表现出海马形态的显著变化，这可能是由于齿状回（DG）中新生神经元的产生和迁移受损。为了理解其背后的机制，我们研究了NCALD相互作用组，并鉴定了丝裂原活化蛋白激酶10（MAP 3 K10）作为一种新的NCALD相互作用伴侣。MAP 3 K10是c-Jun N-末端激酶（JNK）的上游激活激酶，其调节成体神经发生。引人注目的是，JNK活化在Ncald（KO/KO）脑中显著上调。相反，无论是成年神经发生，也不JNK激活杂合子Ncald缺失改变。总之，我们的研究确定了NCALD和海马中成人神经发生之间的新联系，可能通过MAP 3 K10-JNK通路，并强调了使用NCALD减少作为SMA治疗选择的安全性。
Neurocalcin delta (NCALD) is a brain-enriched neuronal calcium sensor and its reduction acts protective against spinal muscular atrophy (SMA). However, the physiological function of NCALD and implications of NCALD reduction are still elusive. Here, we analyzed the ubiquitous Ncald knockout in homozygous (Ncald(KO/KO)) and heterozygous (Ncald(KO/WT)) mice to unravel the physiological role of NCALD in the brain and to study whether 50% NCALD reduction is a safe option for SMA therapy. We found that Ncald(KO/KO) but not Ncald(KO/WT) mice exhibit significant changes in the hippocampal morphology, likely due to impaired generation and migration of newborn neurons in the dentate gyrus (DG). To understand the mechanism behind, we studied the NCALD interactome and identified mitogen-activated protein kinase kinase kinase 10 (MAP3K10) as a novel NCALD interacting partner. MAP3K10 is an upstream activating kinase of c-Jun N-terminal kinase (JNK), which regulates adult neurogenesis. Strikingly, the JNK activation was significantly upregulated in the Ncald(KO/KO) brains. Contrary, neither adult neurogenesis nor JNK activation were altered by heterozygous Ncald deletion. Taken together, our study identifies a novel link between NCALD and adult neurogenesis in the hippocampus, possibly via a MAP3K10-JNK pathway and emphasizes the safety of using NCALD reduction as a therapeutic option for SMA.