mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies.
Antonella Caccamo,Andrea Magrì,David X. Medina,Elena V. Wisely,Manuel F. López-Aranda,Alcino J. Silva,Salvatore Oddo +6 more
TLDR
It is shown that increasing mTOR signaling facilitates tau pathology, while reducing mTOR pathway signaling ameliorates t Tau pathology.Abstract:
Accumulation of tau is a critical event in several neurodegenerative disorders, collectively known as tauopathies, which include Alzheimer's disease and frontotemporal dementia. Pathological tau is hyperphosphorylated and aggregates to form neurofibrillary tangles. The molecular mechanisms leading to tau accumulation remain unclear and more needs to be done to elucidate them. Age is a major risk factor for all tauopathies, suggesting that molecular changes contributing to the aging process may facilitate tau accumulation and represent common mechanisms across different tauopathies. Here, we use multiple animal models and complementary genetic and pharmacological approaches to show that the mammalian target of rapamycin (mTOR) regulates tau phosphorylation and degradation. Specifically, we show that genetically increasing mTOR activity elevates endogenous mouse tau levels and phosphorylation. Complementary to it, we further demonstrate that pharmacologically reducing mTOR signaling with rapamycin ameliorates tau pathology and the associated behavioral deficits in a mouse model overexpressing mutant human tau. Mechanistically, we provide compelling evidence that the association between mTOR and tau is linked to GSK3β and autophagy function. In summary, we show that increasing mTOR signaling facilitates tau pathology, while reducing mTOR signaling ameliorates tau pathology. Given the overwhelming evidence that reducing mTOR signaling increases lifespan and healthspan, the data presented here have profound clinical implications for aging and tauopathies and provide the molecular basis for how aging may contribute to tau pathology. Additionally, these results provide preclinical data indicating that reducing mTOR signaling may be a valid therapeutic approach for tauopathies.read more
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Ageing, neurodegeneration and brain rejuvenation
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Roles of tau protein in health and disease.
TL;DR: It is important to fully understand the range of neuronal functions attributed to tau, since this will provide vital information on its involvement in the development and pathogenesis of disease, and enable determination of which critical molecular pathways should be targeted by potential therapeutic agents developed for the treatment of tauopathies.
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Systemic administration of epothilone B promotes axon regeneration after spinal cord injury
Jörg Ruschel,Farida Hellal,Kevin C. Flynn,Sebastian Dupraz,David A. Elliott,Andrea Tedeschi,Margaret L. Bates,Christopher Sliwinski,Gary A. Brook,Kristina Dobrindt,Michael Peitz,Oliver Brüstle,Michael D. Norenberg,Armin Blesch,Norbert Weidner,Mary Bartlett Bunge,John L. Bixby,Frank Bradke +17 more
TL;DR: Delayed systemic administration of a blood-brain barrier–permeable microtubule-stabilizing drug, epothilone B (epoB), decreased scarring after rodent spinal cord injury (SCI) and promoted axon regeneration and improved motor function after SCI.
Journal ArticleDOI
mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases
Michela Palmieri,Rituraj Pal,Hemanth R. Nelvagal,Parisa Lotfi,Gary R. Stinnett,Michelle L. Seymour,Arindam Chaudhury,Lakshya Bajaj,Vitaliy V. Bondar,Laura Bremner,Usama Saleem,Dennis Y. Tse,Dennis Y. Tse,Deepthi Sanagasetti,Samuel M. Wu,Joel R. Neilson,Fred A. Pereira,Robia G. Pautler,George G. Rodney,Jonathan D. Cooper,Marco Sardiello +20 more
TL;DR: It is shown that Akt phosphorylates T FEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEb inhibitor.
Journal ArticleDOI
The Autophagy-Lysosomal Pathway in Neurodegeneration: A TFEB Perspective.
TL;DR: The regulation of the ALP and TFEB and their impact on neurodegenerative diseases is reviewed and the perspective on the complex role of autophagy and T FEB in disease pathogenesis and its therapeutic implications through the examination of prion disease is offered.
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