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Dual mTORC1/mTORC2 blocker as a possible therapy for tauopathy in cellular model

Abstract

Tauopathy comprises a group of disorders caused by abnormal aggregates of tau protein. In these disorders phosphorylated tau protein tends to accumulate inside neuronal cells (soma) instead of the normal axonal distribution of tau. A suggested therapeutic strategy for tauopathy is to induce autophagy to increase the ability to get rid of the unwanted tau aggregates. One of the key controllers of autophagy is mTOR. Blocking mTOR leads to stimulation of autophagy. Recently, unravelling molecular structure of mTOR showed that it is formed of two subunits: mTORC1/C2. So, blocking both subunits of mTOR seems more attractive as it will explore all abilities of mTOR molecule. In the present study, we report using pp242 which is a dual mTORC1/C2 blocker in cellular model of tauopathy using LUHMES cell line. Adding fenazaquin to LUHMES cells induced tauopathy in the form of increased phospho tau aggregates. Moreover, fenazaquin treated cells showed the characteristic somatic redistribution of tau. PP242 use in the present tauopathy model reversed the pathology significantly without observable cellular toxicity for the used dosage of 1000 nM. The present study suggests the possible use of pp242 as a dual mTOR blocker to treat tauopathy.

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Acknowledgments

The present work was funded by the research grant of Parkinson’s and Movement Disorders Foundation (PMDF, USA-2015), Mansoura University Competitive Research Grants (EGYPT-2016) and International society for Neurochemistry CAEN Category 1B (2017).

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Authors and Affiliations

Authors

Contributions

A – research concept and design; B – cell culture and data generation; C – data analysis and interpretation; D – writing the article; E – critical revision of the article; F – final approval of article.

• Mohamed Salama: A, B, C, D, E, F

• Mahmoud Elhussiny: B, C,

• Alshimaa Magdy: B,C

• Ahmed G Omran: B, C

• Aziza Alsayed: B, C

• Ramy Ashry: B,C

• Wael Mohamed: A, D, E, F

Corresponding author

Correspondence to Mohamed Salama.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Salama, M., Elhussiny, M., Magdy, A. et al. Dual mTORC1/mTORC2 blocker as a possible therapy for tauopathy in cellular model. Metab Brain Dis 33, 583–587 (2018). https://doi.org/10.1007/s11011-017-0137-7

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  • DOI: https://doi.org/10.1007/s11011-017-0137-7

Keywords

  • Tau
  • mTOR
  • pp242
  • Dual blocker