Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice.
Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice.
复制标题
异常的miR-339-5p/神经元信号传导导致突变早老素小鼠的前驱期神经元钙稳态失衡
DOI：
10.1172/jci149160
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发表时间：
2022-04-15
期刊：
影响因子：
--
通讯作者：
Sun S
中科院分区：
文献类型：
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作者：
Zou HY;Guo L;Zhang B;Chen S;Wu XR;Liu XD;Xu XY;Li BY;Chen S;Xu NJ;Sun S
蘑菇脊柱丢失和钙平衡失调是与年龄相关的神经变性的早期标志事件，如阿尔茨海默病（AD），这与认知脑区早期病理中的神经元过度活跃有关。然而，这些关键事件是如何在分子水平上触发发生在疾病初始阶段的神经元异常的，仍然是难以捉摸的。在本研究中，我们在家族性AD （FAD）小鼠模型的早老素-1 M146V敲入蛋白（PSEN1-M146V KI）中发现了下调的miR-339-5p及其上调的靶蛋白神经元蛋白（Nnat）。抑制miR-339-5p或Nnat的过表达会在PSEN1突变的皮质神经元中重现脊柱丢失和内质网钙超载。相反，miR-339-5p过表达或Nnat敲低均可恢复脊柱形态发生和钙稳态。我们在客体认知过程中使用纤维光度法记录，进一步证明PSEN1突变体导致脾后皮层神经元反应习惯化缺陷，这可以通过恢复miR-339-5p/Nnat途径来挽救。因此，我们的研究结果揭示了miR-339-5p/Nnat通路在FAD中的关键作用，可能作为早期发病机制的潜在诊断和治疗靶点。
Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer’s disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.