Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin
- University Grenoble Alpes, France
- Sorbonne Université, France
- Institut du Cerveau et de la Moelle épinière, ICM, France
Abstract
Studies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the evidence has not been consistent. In particular, signaling pathways controlling APP transport to the synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), the scaffolding protein involved in Huntington's disease, regulates neuritic transport of APP, we used a microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the pre- and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic density. Ablating in vivo HTT phosphorylation in APPPS1 mice, which overexpress APP, reduced presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Jean-Christophe Deloulme
Funding
Agence Nationale de la Recherche (ANR-12-MALZ-0004 HuntAbeta)
- Frédéric Saudou
Agence Nationale de la Recherche (ANR-15-IDEX-02 NeuroCoG)
- Frédéric Saudou
Agence Nationale de la Recherche (ANR-10-IAIHU-06)
- Marie-Claude Potier
Fondation pour la Recherche Médicale (DEQ20170336752)
- Sandrine Humbert
Fondation pour la Recherche Médicale (FDT201904008035)
- Hélène Marine Vitet
Fondation pour la Recherche Médicale (DEI20151234418)
- Frédéric Saudou
Fondation pour la Recherche sur le Cerveau
- Frédéric Saudou
INSERM (AGEMED)
- Frédéric Saudou
Fondation Bettencourt Schueller
- Frédéric Saudou
Association Huntington France
- Hélène Marine Vitet
Agence Nationale de la Recherche (ANR-12-MALZ-0004 HuntAbeta)
- Marie-Claude Potier
INSERM (AGEMED)
- Sandrine Humbert
Agence Nationale de la Recherche (ANR-14-CE35-0027-01 PASSAGE)
- Frédéric Saudou
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animals were held in accordance with the French Animal Welfare Act and the EU legislation (Council Directive 86/609/EEC) and the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. The French Ministry of Agriculture and the local ethics committee gave specific authorization (authorization no. 04594.02) to BD to conduct the experiments described in the present study.
Copyright
© 2020, Bruyère et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin
eLife 9:e56371.
https://doi.org/10.7554/eLife.56371
Further reading
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- Cell Biology
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Background:
It has been reported that loss of PCBP2 led to increased reactive oxygen species (ROS) production and accelerated cell aging. Knockdown of PCBP2 in HCT116 cells leads to significant downregulation of fibroblast growth factor 2 (FGF2). Here, we tried to elucidate the intrinsic factors and potential mechanisms of bone marrow mesenchymal stromal cells (BMSCs) aging from the interactions among PCBP2, ROS, and FGF2.
Methods:
Unlabeled quantitative proteomics were performed to show differentially expressed proteins in the replicative senescent human bone marrow mesenchymal stromal cells (RS-hBMSCs). ROS and FGF2 were detected in the loss-and-gain cell function experiments of PCBP2. The functional recovery experiments were performed to verify whether PCBP2 regulates cell function through ROS/FGF2-dependent ways.
Results:
PCBP2 expression was significantly lower in P10-hBMSCs. Knocking down the expression of PCBP2 inhibited the proliferation while accentuated the apoptosis and cell arrest of RS-hBMSCs. PCBP2 silence could increase the production of ROS. On the contrary, overexpression of PCBP2 increased the viability of both P3-hBMSCs and P10-hBMSCs significantly. Meanwhile, overexpression of PCBP2 led to significantly reduced expression of FGF2. Overexpression of FGF2 significantly offset the effect of PCBP2 overexpression in P10-hBMSCs, leading to decreased cell proliferation, increased apoptosis, and reduced G0/G1 phase ratio of the cells.
Conclusions:
This study initially elucidates that PCBP2 as an intrinsic aging factor regulates the replicative senescence of hBMSCs through the ROS-FGF2 signaling axis.
Funding:
This study was supported by the National Natural Science Foundation of China (82172474).
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Autophagy-related gene 6 (ATG6) plays a crucial role in plant immunity. Nonexpressor of pathogenesis-related genes 1 (NPR1) acts as a signaling hub of plant immunity. However, the relationship between ATG6 and NPR1 is unclear. Here, we find that ATG6 directly interacts with NPR1. ATG6 overexpression significantly increased nuclear accumulation of NPR1. Furthermore, we demonstrate that ATG6 increases NPR1 protein levels and improves its stability. Interestingly, ATG6 promotes the formation of SINCs (SA-induced NPR1 condensates)-like condensates. Additionally, ATG6 and NPR1 synergistically promote the expression of pathogenesis-related genes. Further results showed that silencing ATG6 in NPR1-GFP exacerbates Pst DC3000/avrRps4 infection, while double overexpression of ATG6 and NPR1 synergistically inhibits Pst DC3000/avrRps4 infection. In summary, our findings unveil an interplay of NPR1 with ATG6 and elucidate important molecular mechanisms for enhancing plant immunity.
