Dual mTORC1/mTORC2 blocker as a possible therapy for tauopathy in cellular model
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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.
KeywordsTau mTOR pp242 Dual blocker
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).
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
Compliance with ethical standards
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
- Escobar-Khondiker M, Höllerhage M, Muriel M, Champy P, Bach A, Depienne C, Respondek G, Yamada ES, Lannuzel A, Yagi T, Hirsch EC, Oertel WH, Jacob R, Michel PP, Ruberg M, Höglinger GU (2007) Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J Neurosci 27:7827–7837CrossRefPubMedGoogle Scholar
- Ludolph AC, Kassubek J, Landwehrmeyer BG, Mandelkow E, Mandelkow EM, Burn DJ, Caparros-Lefebvre D, Frey KA, de Yebenes JG, Gasser T, Heutink P, Höglinger G, Jamrozik Z, Jellinger KA, Kazantsev A, Kretzschmar H, Lang AE, Litvan I, Lucas JJ, PL MG, Melquist S, Oertel W, Otto M, Paviour D, Reum T, Saint-Raymond A, Steele JC, Tolnay M, Tumani H, van Swieten JC, Vanier MT, Vonsattel JP, Wagner S, Wszolek ZK, Reisensburg Working Group for Tauopathies With Parkinsonism (2009) Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options. Eur J Neurol 16(3):297–309CrossRefPubMedPubMedCentralGoogle Scholar
- Skovronsky DM (2007) Tau in Parkinsonian Diseases. In: Dawson TM (ed) Parkinson's disease genetics and pathogenesis. Informa healthcare, New York, pp 187–198Google Scholar
- Tang Z, Bereczki E, Zhang H, Wang S, Li C, Ji X, Branca RM, Lehtiö J, Guan Z, Filipcik P, Xu S, Winblad B, Pei JJ (2013) Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease. J Biol Chem 288(22):15556–15570CrossRefPubMedPubMedCentralGoogle Scholar
- Wang ZG, Wang Y, Huang Y, Lu Q, Zheng L, Hu D, Feng WK, Liu YL, Ji KT, Zhang HY, XB F, Li XK, Chu MP, Xiao J (2015) bFGF regulates autophagy and ubiquitinated protein accumulation induced by myocardial ischemia/reperfusion via the activation of the PI3K/Akt/mTOR pathway. Sci Rep 5:9287–9298CrossRefPubMedPubMedCentralGoogle Scholar