Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain

Ye, Hui; Ojelade, Shamsideen A.; Li‐Kroeger, David; Zuo, Zhuang; Wang, Liping; Li, Yarong; Gu, Junhao; Tepaß, Ulrich; Rodal, Avital A.; Bellen, Hugo J.; Liu, Zhandong

doi:10.1101/788711

Cited by 3 publications

(1 citation statement)

References 96 publications

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“…Vps29 mutation induces mis-localization of the retromer to endosomes in the soma, which inhibits synaptic transmission (Ye et al, 2020), and genetic deficiency of SORCS2 impaired the glutamate NMDA receptor 2A (GluN2A) subunit regulating synaptic plasticity trafficking (Ma et al, 2017), other retromer components may contribute to diabetes-mediated AD-like phenotype. In conclusion, we demonstrated that APP processing and tau phosphorylation are modulated by VPS26a, and down-regulated by ROS/NF-κB/ DNMT1-mediated promoter hypermethylation in neuronal cells exposed to high glucose, which contributes to synaptic deficits, astrocyte over-activation, and cognitive impairment (Figure S8).…”

Section: Discussionmentioning

confidence: 99%

High glucose‐mediated VPS26a down‐regulation dysregulates neuronal amyloid precursor protein processing and tau phosphorylation

Chae

Choi

Jung

et al. 2022

British J Pharmacology

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Background and Purpose: The relationship between hyperglycaemia-induced retromer dysfunction impairing intracellular trafficking and Alzheimer's disease (AD) remains unclear, although diabetes mellitus (DM) is considered a risk factor for AD. Here, we investigated the effects of high glucose on the retromer and defined the dysregulation of mechanisms of amyloid precursor protein (APP) processing and tau phosphorylation.Experimental Approach: We used human induced-pluripotent stem cell-derived neuronal differentiated cells and SH-SY5Ys exposed to high glucose to identify the underlying mechanisms. Streptozotocin-induced diabetic mice were used to elucidate whether the retromer contributes to the AD-like pathology.Key Results: We found that vacuolar protein sorting-associated protein 26a (VPS26a) was decreased in the hippocampus of diabetic mice and high glucosetreated human neuronal cells. High glucose down-regulated VPS26a through ROS/NF-κB/DNA methyltransferase1-mediated promoter hypermethylation.VPS26a recovery blocked retention of APP and cation-independent mannose-6-phosphate receptor in endosomes and promoted transport to the trans-Golgi, which decreased Aβ levels, and improved cathepsin D activity, reducing p-tau levels, respectively. Retromer enhancement ameliorated synaptic deficits, astrocyte overactivation, and cognitive impairment in diabetic mice. Conclusion and Implications:In conclusion, VPS26a is a promising candidate for the inhibition of DM-associated AD pathogenesis by modulating APP processing and tau phosphorylation.

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Section: Discussionmentioning

confidence: 99%

High glucose‐mediated VPS26a down‐regulation dysregulates neuronal amyloid precursor protein processing and tau phosphorylation

Chae

Choi

Jung

et al. 2022

British J Pharmacology

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A quick and laidback way to detect the internal structure of the Drosophila eye: An alternative to cryosectioning

Sahu

Karmakar

Saha

et al. 2023

Reproductive Toxicology

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Retromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau

et al. 2022

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Alteration of the levels, localization or post-translational processing of the microtubule associated protein Tau is associated with many neurodegenerative disorders. Here we develop adult-onset models for human Tau (hTau) toxicity in Drosophila that enable age-dependent quantitative measurement of central nervous system synapse loss and axonal degeneration, in addition to effects upon lifespan, to facilitate evaluation of factors that may contribute to Tau-dependent neurodegeneration. Using these models, we interrogate the interaction of hTau with the retromer complex, an evolutionarily conserved cargo-sorting protein assembly, whose reduced activity has been associated with both Parkinson’s and late onset Alzheimer’s disease. We reveal that reduction of retromer activity induces a potent enhancement of hTau toxicity upon synapse loss, axon retraction and lifespan through a specific increase in the production of a C-terminal truncated isoform of hTau. Our data establish a molecular and subcellular mechanism necessary and sufficient for the depletion of retromer activity to exacerbate Tau-dependent neurodegeneration.

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Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain

Cited by 3 publications

References 96 publications

High glucose‐mediated VPS26a down‐regulation dysregulates neuronal amyloid precursor protein processing and tau phosphorylation

High glucose‐mediated VPS26a down‐regulation dysregulates neuronal amyloid precursor protein processing and tau phosphorylation

A quick and laidback way to detect the internal structure of the Drosophila eye: An alternative to cryosectioning

Retromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau

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