Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice
Hao-Yu Zou, … , Nan-Jie Xu, Suya Sun
Hao-Yu Zou, … , Nan-Jie Xu, Suya Sun
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e149160. https://doi.org/10.1172/JCI149160.
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Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice

Abstract

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.

Authors

Hao-Yu Zou, Lin Guo, Bei Zhang, Si Chen, Xin-Rong Wu, Xian-Dong Liu, Xin-Yu Xu, Bin-Yin Li, Shengdi Chen, Nan-Jie Xu, Suya Sun

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Figure 7

Inhibition of Nnat rescues behavioral deficits in spatial and object cognition.

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Inhibition of Nnat rescues behavioral deficits in spatial and object cog...
(A) Schematic of experimental design. Viral injections were given to 8-week-old mice, and BMTs and NORT (same as Figure 5A) were performed after 4 months. (B) For the BMT, latency to the target hole was recorded. n = 8 mice for Nnat-overexpressed WT group; n = 10 mice for Nnat-overexpressed KI group; n = 15 mice for other 4 groups. (C) Representative images of exploring paths of different groups on day 5. (D and E) Latency to the target hole and the number of visits of the error holes on day 5. n = 8 mice for Nnat-overexpressed WT group; n = 10 mice for Nnat-overexpressed KI group; n = 15 mice for other 4 groups. (F) Left: representative heatmaps from 6 independent experiments with similar results depicting time of object exploration. White circles represent the location of novel objects (N) and familiar objects (F). Right: 2-month-old mice showed no significant differences in discrimination index in the NORT. n = 16 mice for WT control group; n = 10 mice for WT mice treated with shNnat; n = 13 mice for Nnat-overexpressed KI group; n = 15 mice for other 3 groups. For experiment process, also see Figure 5A. (G) Left: representative heatmaps from 4 independent experiments depicting time of object exploration. White circles represent the location of novel objects and familiar objects. Right: discrimination index of 6-month-old mice in the NORT. n = 16 mice for WT mice treated with shNnat group; n = 15 mice for each group. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001, 2-way ANOVA, Tukey’s test.