A new study reports that rapamycin, which is normally used for immunosuppression in organ transplantation, could be used to treat neurodegeneration by inhibiting mTOR and preserving ATP levels in neurons
Neurodegeneration describes the progressive deterioration in an individual’s cognitive functions. This feature often manifests as a neurodegenerative disease, such as Alzheimer’s and Parkinson’s, and is detrimental to the health of many individuals, no matter the age. Leigh syndrome, for example, is known to affect 1 in 40 000 newborns in the United States. This neurodegenerative disease is characterized by the gradual loss of mental and locomotor skills in infants, which often culminates in death due to respiratory failure. Of the aforementioned cases of Leigh syndrome, a quarter is due to mutated DNA in the mitochondria (the energy-producing component of cells) which then affects genes responsible for quality regulation. The resulting mitochondrial dysfunction leads to decreased levels of available cellular energy in the form of adenosine triphosphate (ATP), often known as the energy currency of the cell, and results in subsequent cell death.
In a recent study performed by a group of researchers in the United States and published in eLIFE, the effects of the drug rapamycin on neuronal ATP levels and protein synthesis were examined. It was demonstrated that rapamycin-induced mTOR inhibition in human neurons had successfully preserved ATP levels by reducing the level of protein synthesis, specifically when oxidative phosphorylation was disabled.
Oxidative phosphorylation is a metabolic pathway through which an organism produces cellular energy. This process involves protein complexes along the inner mitochondrial membrane which carry out electron transport to an oxygen molecule, hence the term “oxidative”. The flow of electrons also leads to the formation of potential energy through an electrochemical gradient. Also embedded in the inner mitochondrial membrane is a large enzyme named ATP synthase, which uses the stored energy to generate ATP through a phosphorylation reaction. Through this process, ATP is made available for a variety of cell functions.
Signalling pathways are of critical importance as they are part of the governing system that controls cellular processes. In one particular pathway, mTOR (mammalian or mechanistic target of rapamycin) is a protein kinase responsible for regulating cell growth and proliferation by promoting protein synthesis and inhibiting non-apoptotic cell death or autophagy. It is necessary for cells in the body to regulate the balance between protein synthesis and cell degradation. This equilibrium, however, is frequently disturbed in neurodegenerative diseases. A compound produced by Streptomyces hygroscopicus, called rapamycin, has offered hope towards ameliorating this effect. Rapamycin is able to act by directly binding and inhibiting mTOR, the protein that adjusts the amount of nutrients and energy available for producing new proteins. Normally, rapamycin, also known as sirolimus, is used towards preventing rejection of organ transplantations as it induces immunosuppression in humans.
In the lab, researchers had employed three different mitochondrial drugs to imitate defects in oxidative phosphorylation, in order to test how rapamycin affects ATP levels in neurons. Higher levels of ATP after treatment would suggest that rapamycin is able to conserve cellular energy, and therefore save cells from degrading. The experiments also involved neurons grown in the lab, which resembled those of maternally inherited Leigh Syndrome (MILS) patients, in order to develop an induced pluripotent stem (iPS) cell model. This was used to determine the potential of rapamycin for therapeutic use. MILS neurons have impaired oxidative phosphorylation and thus release a significantly lower amount of ATP for cellular function. Remarkably, when the damaged neurons were treated with rapamycin, protein production had decreased whereas ATP levels had increased, saving the neuronal cells from degradation.
Overall, researchers observed favourable effects of using rapamycin in mitochondria inhibitor-treated neurons as well as in the iPSC-based model of MILS. Although promising for therapeutic use for mitochondria-related neurodegenerative diseases, researchers note that there are possible negative effects associated with long-term usage. Further investigation needs to be conducted using animal models to fully assess the scope of its potential.
Written By: Michelle Tu, BSc