GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions
| العنوان: | GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions |
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| المؤلفون: | Huazhang Zhu, Zhijun He, Wencong Wang, Yangfan Yang, Ying Ying, Dan-dan Wang, Xingsheng Shu, Weizhen Zhang, Yingying Zhao, Xiaomei Wang |
| المصدر: | Molecular Neurodegeneration Molecular Neurodegeneration, Vol 13, Iss 1, Pp 1-17 (2018) |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Retinal Ganglion Cells, lcsh:Geriatrics, lcsh:RC346-429, Synapse, chemistry.chemical_compound, 0302 clinical medicine, Diabetic retinopathy, Medicine, Synaptic and mitochondrial dysfunction, Phosphorylation, biology, Neurodegeneration, Retinal neurodegeneration, Mitochondria, Tauopathies, Tauopathy, Research Article, Tau protein, Context (language use), tau Proteins, Retinal ganglion, Retina, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, Animals, Hyperphosphorylated tau, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Glycogen Synthase Kinase 3 beta, business.industry, Estriol, Neurotoxicity, GSK3β, Retinal, medicine.disease, Mice, Inbred C57BL, lcsh:RC952-954.6, Disease Models, Animal, 030104 developmental biology, chemistry, biology.protein, Evoked Potentials, Visual, Neurology (clinical), sense organs, business, Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | Background Although diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Key molecules involved in this process remain poorly defined. The microtubule-associated protein tau is a critical mediator of neurotoxicity in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the effect of tau, if any, in the context of diabetes-induced retinal neurodegeneration has yet to be ascertained. Here, we investigate the changes and putative roles of endogeneous tau in diabetic retinal neurodegeneration. Methods To this aim, we combine clinically used electrophysiological techniques, i.e. pattern electroretinogram and visual evoked potential, and molecular analyses in a well characterized high-fat diet (HFD)-induced mouse diabetes model in vivo and primary retinal ganglion cells (RGCs) in vitro. Results We demonstrate for the first time that tau hyperphosphorylation via GSK3β activation causes vision deficits and synapse loss of RGCs in HFD-induced DR, which precedes retinal microvasculopathy and RGCs apoptosis. Moreover, intravitreal administration of an siRNA targeting to tau or a specific inhibitor of GSK3β reverses synapse loss and restores visual function of RGCs by attenuating tau hyperphosphorylation within a certain time frame of DR. The cellular mechanisms by which hyperphosphorylated tau induces synapse loss of RGCs upon glucolipotoxicity include i) destabilizing microtubule tracks and impairing microtubule-dependent synaptic targeting of cargoes such as mRNA and mitochondria; ii) disrupting synaptic energy production through mitochondria in a GSK3β-dependent manner. Conclusions Our study proposes mild retinal tauopathy as a new pathophysiological model for DR and tau as a novel therapeutic target to counter diabetic RGCs neurodegeneration occurring before retinal vasculature abnormalities. Electronic supplementary material The online version of this article (10.1186/s13024-018-0295-z) contains supplementary material, which is available to authorized users. |
| تدمد: | 1750-1326 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::290d3e76c6303ca29334eb573906ccc0Test https://pubmed.ncbi.nlm.nih.gov/30466464Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....290d3e76c6303ca29334eb573906ccc0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17501326 |
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