Stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathies.

Autor: Akwa Y; Department of Diseases and Hormones of the Nervous System, U1195 INSERM - Université Paris-Saclay, Le Kremlin-Bicêtre, France., Di Malta C; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.; Department. of Translational Medicine, Medical Genetics, Federico II University, Naples, Italy., Zallo F; Achucarro Basque Center for Neuroscience, Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU) and Centro de Investigación en Red de Enfermedades, Neurodegenerativas (CIBERNED), Leioa, Spain., Gondard E; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., Lunati A; Institut Professeur Baulieu, Le Kremlin-Bicêtre, France., Diaz-de-Grenu LZ; Achucarro Basque Center for Neuroscience, Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU) and Centro de Investigación en Red de Enfermedades, Neurodegenerativas (CIBERNED), Leioa, Spain.; TECNALIA, Basque Research and Technology Alliance (BRTA), Derio, Spain., Zampelli A; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy., Boiret A; Department of Diseases and Hormones of the Nervous System, U1195 INSERM - Université Paris-Saclay, Le Kremlin-Bicêtre, France.; Institut Professeur Baulieu, Le Kremlin-Bicêtre, France., Santamaria S; Cellular Electron Microscopy Lab, DIMES, Department of Experimental Medicine, University of Genoa, Genova, Italy., Martinez-Preciado M; Achucarro Basque Center for Neuroscience, Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU) and Centro de Investigación en Red de Enfermedades, Neurodegenerativas (CIBERNED), Leioa, Spain., Cortese K; Cellular Electron Microscopy Lab, DIMES, Department of Experimental Medicine, University of Genoa, Genova, Italy., Kordower JH; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.; College of Liberal Arts and Sciences, Arizona State University, Tempe, AZ, USA., Matute C; Achucarro Basque Center for Neuroscience, Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU) and Centro de Investigación en Red de Enfermedades, Neurodegenerativas (CIBERNED), Leioa, Spain., Lozano AM; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.; Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada., Capetillo-Zarate E; Achucarro Basque Center for Neuroscience, Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU) and Centro de Investigación en Red de Enfermedades, Neurodegenerativas (CIBERNED), Leioa, Spain.; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain., Vaccari T; Department of Biosciences, University of Milan, Milan, Italy., Settembre C; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.; Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy., Baulieu EE; Department of Diseases and Hormones of the Nervous System, U1195 INSERM - Université Paris-Saclay, Le Kremlin-Bicêtre, France.; Institut Professeur Baulieu, Le Kremlin-Bicêtre, France., Tampellini D; Department of Diseases and Hormones of the Nervous System, U1195 INSERM - Université Paris-Saclay, Le Kremlin-Bicêtre, France.; Institut Professeur Baulieu, Le Kremlin-Bicêtre, France.
Jazyk: angličtina
Zdroj: Autophagy [Autophagy] 2023 Feb; Vol. 19 (2), pp. 660-677. Date of Electronic Publication: 2022 Jul 22.
DOI: 10.1080/15548627.2022.2095791
Abstrakt: Synapses represent an important target of Alzheimer disease (AD), and alterations of their excitability are among the earliest changes associated with AD development. Synaptic activation has been shown to be protective in models of AD, and deep brain stimulation (DBS), a surgical strategy that modulates neuronal activity to treat neurological and psychiatric disorders, produced positive effects in AD patients. However, the molecular mechanisms underlying the protective role(s) of brain stimulation are still elusive. We have previously demonstrated that induction of synaptic activity exerts protection in mouse models of AD and frontotemporal dementia (FTD) by enhancing the macroautophagy/autophagy flux and lysosomal degradation of pathological MAPT/Tau. We now provide evidence that TFEB (transcription factor EB), a master regulator of lysosomal biogenesis and autophagy, is a key mediator of this cellular response. In cultured primary neurons from FTD-transgenic mice, synaptic stimulation inhibits MTORC1 signaling, thus promoting nuclear translocation of TFEB, which, in turn, induces clearance of MAPT/Tau oligomers. Conversely, synaptic activation fails to promote clearance of toxic MAPT/Tau in neurons expressing constitutively active RRAG GTPases, which sequester TFEB in the cytosol, or upon TFEB depletion. Activation of TFEB is also confirmed in vivo in DBS-stimulated AD mice. We also demonstrate that DBS reduces pathological MAPT/Tau and promotes neuroprotection in Parkinson disease patients with tauopathy. Altogether our findings indicate that stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau. This mechanism, underlying the protective effect of DBS, provides encouraging support for the use of synaptic stimulation as a therapeutic treatment against tauopathies. Abbreviations: 3xTg-AD: triple transgenic AD mice; AD: Alzheimer disease; CSA: cyclosporine A; DBS: deep brain stimulation; DIV: days in vitro ; EC: entorhinal cortex; FTD: frontotemporal dementia; gLTP: glycine-induced long-term potentiation; GPi: internal segment of the globus pallidus; PD: Parkinson disease; STN: subthalamic nucleus; TFEB: transcription factor EB.
Databáze: MEDLINE
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