In 1972, Easter Island, called Rapa Nui, famous for its moai statues, offered a new wonder: the discovery of the drug rapamycin.
Over the past three decades, rapamycin, which was isolated from soil bacteria, has been applied as an immuno-suppressor in a multitude of ways, including to coat coronary stents and to reduce the immune responses in people who receive organ transplants.
Currently, it’s garnering attention because of its potentials in anti-cancer and neuroprotection as well as anti-aging therapies.
The drug works by targeting a master regulator of cell growth in our cells called mTOR.
When rapamycin targets mTOR, it inhibits cell growth.
This makes a potent anti-cancer drug, since cancer is marked by uncontrolled cell growth.
The inhibition of mTOR also triggers autophagy, a process by which lysosomes, the so-called recycling centers of cells, clean up misfolded proteins and damaged organelles.
These proteins and organelles are then turned into amino acids and sugars for reuse by the cell.
“The main function of the lysosome is to maintain the healthy state of the cell because it degrades the harmful stuff within the cell,” said Xiaoli Zhang, a postdoctoral researcher in the University of Michigan Department of Molecular, Cellular and Developmental Biology.
“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.”
Rapamycin (Fig. 1), first isolated from a strain of Streptomyces hygroscopicus indigenous to Easter Island, is a member of a family of macrolide immunosuppressants used to prevent rejections following organ transplantation via the inhibition of T and B cell proliferation [7–9].
Rapamycin inhibits the mammalian target of rapamycin (mTOR) pathway via direct binding of mTOR Complex 1 (mTORC1) that is a nutrient-sensitive kinase [10, 11].
Therefore, rapamycin is involved in many cellular functions, such as cell growth, proliferation, protein synthesis, and autophagy.
Studies have shown that rapamycin can extend the lifespan of organisms and slow the progression of aging [12, 13].
For example, rapamycin was shown to extend lifespan and retard aging in yeast [14] and mouse [15], respectively.
Moreover, as rapamycin has anti-proliferative effects [16, 17], it may benefit patients with cancer [18, 19], adipogenesis [20, 21], diabetes [22, 23], tuberous sclerosis [24, 25], cardiovascular diseases [26–29], and neurological disorders [30, 31].
In the brain, the most striking effect of rapamycin is its neuroprotective effects, making it a potential therapeutic pharmacological compound to curb neurodegenerative disorders [32] such as Alzheimer’s disease [6, 12, 33, 34], Parkinson’s disease [35, 36], and Huntington’s disease [37, 38].
The underlying neuroprotective mechanisms of rapamycin are thought to be related to its effects on autophagy enhancement [39–41].
The chemical structure of rapamycin.
Autophagy
Autophagy is a lysosome-mediated, self-digesting degradation mechanism that involves the removal of damaged organelles and misfolded or nonfunctional proteins [42, 43].
Autophagy is essential for cell growth, survival, differentiation, development as well as protein homeostasis, and maintains a balance between the synthesis, degradation, and subsequent recycling of cellular products [44, 45].
Autophagy plays an important role in a variety of pathologies such as cancer [46, 47] and neurodegeneration [6].
Numerous studies have shown that the process of autophagy is negatively regulated by the activation of mTOR because mTORC1 and Atg1/ULK complexes can coordinately regulate autophagy in response to pathophysiological stress [48–51].
Rapamycin and neuroprotection in Alzheimer’s disease
Increasing evidence indicates that rapamycin is an effective inhibitor of the neurodegeneration that occurs in AD.
Evidence includes: 1) rapamycin inhibition of mTOR improves AD-linked cognitive deficits [12, 52]; 2) rapamycin enhancement of autophagy reduces Aβ accumulation [6, 34]; and 3) rapamycin enhancement of autophagy attenuates tau hyper-phosphorylation [53, 54]. Fig. 2 summarizes the potential protective mechanisms of rapamycin in AD.
Scheme showing potential mechanisms by which rapamycin ameliorates Alzheimer’s-like cognitive deficits. The mechanism primarily includes: anti-aging effects, anti-oxidative stress and anti- neuroinflammation properties, enhancement of autophagy, and inhibition of both Aβ accumulation and tau hyper-phosphorylation.
Researchers have long thought that rapamycin targets more than one cellular pathway.
Now, Zhang and her fellow researchers have discovered which pathway it is – a calcium ion channel on the lysosomal membrane called TRPML1.
The discovery potentially expands uses for rapamycin. Their results are published in PLOS Biology.
Autophagy is crucial to cellular health, serving as the recycling pathway for maintaining protein and organelle quality.
Cells become cluttered with dysfunctional proteins and organelles during the natural process of aging, and especially in neurodegenerative diseases such as Alzheimer’s Disease and Parkinson’s Disease.
Autophagy is closely dependent on lysosomal activity.
TRPML1 as the main calcium channel on the lysosome is critical in regulating lysosomal function.
“Without this channel, you get neurodegeneration,” said Haoxing Xu, principal investigator of the study. “If you stimulate the channel, it’s anti-neurodegeneration.”
Lead authors Zhang and Wei Chen investigated TRPML1 by using a state-of-art technique called a lysosome patch clamp. When the research team applied rapamycin to lysosomes, they could see the channel is opened by rapamycin no matter whether mTOR was active or deactivated, indicating that rapamycin activates TRPML1 channel independent of mTOR activity.
Most importantly, the team found that autophagy was enhanced by rapamycin dependent on TRPML1, because in the TRPML1-defective cells, autophagy could no longer be triggered by rapamycin.
“We think lysosomal TRPML1 may contribute significantly to the neuroprotective and anti-aging effects of rapamycin,” Chen said.
“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.”
More information: Xiaoli Zhang et al. Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR, PLOS Biology(2019). DOI: 10.1371/journal.pbio.3000252
Journal information: PLoS Biology
Provided by University of Michigan
