Abstract
mTOR inhibition is beneficial in neurodegenerative disease models and its effects are often attributable to the modulation of autophagy and anti-apoptosis. Here, we report a neglected but important bioenergetic effect of mTOR inhibition in neurons. mTOR inhibition by rapamycin significantly preserves neuronal ATP levels, particularly when oxidative phosphorylation is impaired, such as in neurons treated with mitochondrial inhibitors, or in neurons derived from maternally inherited Leigh syndrome (MILS) patient iPS cells with ATP synthase deficiency. Rapamycin treatment significantly improves the resistance of MILS neurons to glutamate toxicity. Surprisingly, in mitochondrially defective neurons, but not neuroprogenitor cells, ribosomal S6 and S6 kinase phosphorylation increased over time, despite activation of AMPK, which is often linked to mTOR inhibition. A rapamycin-induced decrease in protein synthesis, a major energy-consuming process, may account for its ATP-saving effect. We propose that a mild reduction in protein synthesis may have the potential to treat mitochondria-related neurodegeneration.
Highlights
The mTOR complexes coordinate nutrient availability with cell growth and proliferation, promoting protein synthesis and inhibiting autophagy (Laplante and Sabatini, 2012)
After a 6 hr rapamycin treatment of cultured wild type neurons differentiated from human neuroprogenitor cells (NPCs) derived from H9 human ESCs, the ATP level was increased by ~ 13% compared to neurons treated with DMSO as control
Similar effects of rapamycin were observed in neurons treated with rotenone and antimycin-A; but, interestingly, rapamycin was not able to preserve ATP when neurons were treated with CCCP (Figure 1A)
Summary
The mTOR complexes coordinate nutrient availability with cell growth and proliferation, promoting protein synthesis and inhibiting autophagy (Laplante and Sabatini, 2012). Protein homeostasis is often distorted in neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, as well as PolyQ and other proteinopathies, making mTOR an attractive therapeutic target (Boveet al., 2011). Studies from animal models support mTOR inhibition as a promising therapeutic approach for neurodegenerative diseases, several distinct beneficial mechanisms have been proposed. An mTORC1 inhibitor, reduces neuronal cell death in a mouse model of Parkinson’s disease, and decreased synthesis of DDIT4 (DNA-damage-inducible transcript 4) was proposed to provide the protective effect by maintaining AKT pro-survival phosphorylation (Malagelada et al, 2010). Rapamycin strongly suppresses degeneration of dopaminergic neurons in Drosophila with loss of function mutations of PINK1 and PARKIN, genes in which mutations cause human early onset Parkinsonism; importantly, overexpression of 4E-BP, a protein synthesis inhibitor downstream of the mTORC1 pathway, rescues neuronal degeneration in these fly mutants.
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