Posted on May 25, 2019, 4 p.m.
Rampamycin has been getting more attention for potential use in anticancer, neuroprotection, and anti-aging therapies. Rampamycin has been thought to target more than one cellular pathway, this study has discovered which pathway it is: TRPML1 calcium ion channels on the lysosomal membrane.
Since being discovered within soil bacteria from Easter Island rampamycin has been applied as an immuno-suppressor in a number of manners such as coating coronary stents, and helping to reduce immune responses in those who have had organ transplants.
Rampamycin works by targeting mTOR, the master regulator of cell growth within our cells, when targeted rampamycin will inhibit cell growth of mTOR. Being able to inhibit cell growth makes a potent anticancer drug as uncontrolled cell growth is a part of cancer. Inhibiting mTOR also triggers autophagy, which is a process where lysosomes clean up misfolded proteins and damaged organelles, and recycles the proteins and organelles into amino acids and sugars to be reused by the cells.
“The main function of the lysosome is to maintain the healthy state of the cell because it degrades the harmful stuff within the cell. During stress conditions, autophagy can lead to the cell survival by degrading dysfunctional components and providing the building blocks of cells, such as amino acids and lipids.” says Xiaoli Zhang of the University of Michigan.
Autophagy is important to cellular health for maintaining organelle and protein quality as cells can become cluttered with age and especially in neurodegenerative diseases; this process is dependant on lysosomal activity, TRPML is the main calcium channel which is key to regulating lysosomal function.
“Without this channel, you get neurodegeneration, if you stimulate the channel, it’s anti-neurodegeneration.” explains Haoxing Xu, as published in PLOS Biology.
Using lysosome patch clamp techniques TRPML1 was investigated: when rapamycin was applied to lysosomes it was observed to open the channel regardless of whether mTOR was active or not, indicating rapamycin activates the TRPML1 channel independent of mTOR activity. Rapamycin was found to enhance autophagy dependent on TRPML1 because in TRPML1 defective cells rapamycin couldn’t trigger autophagy.
“We think lysosomal TRPML1 may contribute significantly to the neuroprotective and anti-aging effects of rapamycin. The identification of a new target of rapamycin offers an insight in developing the next generation of rapamycin, which will have a more specific effect on neurodegenerative disease.”
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