Using image-based high-throughput screens, HMS researchers, in collaboration with the Shanghai Institute of Organic Chemistry, have identified eight compounds that not only induce autophagy without causing cellular injury but also promote long-lived protein degradation.
Junying Yuan, HMS professor of cell biology and senior author of the study, and her colleagues screened nearly 500 known bioactive compounds before identifying the octet, which have surprising versatility. Of the eight compounds, seven have already been approved by the Food and Drug Administration for various antipsychotic and cardiovascular treatments.
“We wanted to pick out the ones that were truly inducing autophagy,” Yuan said. “We were very surprised that seven of the compounds were already approved by the FDA for drugs.”
Autophagy mediates the degradation of intracellular organelles and long-lived proteins through a lysosome-dependent mechanism. Research has shown that reduction of autophagy leads to the accumulation of misfolded proteins in neurons and may be involved in chronic neurodegenerative diseases.
While the study, appearing in the Nov. 27 Proceedings of the National Academy of Sciences, revealed eight regulators of autophagy, Yuan and colleagues encountered some compounds that only promoted certain aspects of the mechanism. Many compounds, for example, were found to induce autophagy as a result of causing cellular damage. Other compounds induced the accumulation of autophagosomes by blocking downstream lysosomal functions, thereby preventing the degradation process.
“It is important to know if you can find compounds that can increase autophagy without causing cell death,” said Yuan, referring to the popular drugs tamoxifen and rapamycin, which both can activate autophagy but have the side-effect of causing apoptosis.
If researchers can promote the process of autophagy without causing cell injury, they could potentially treat neurodegenerative disorders like Alzheimer’s and Huntington’s diseases.
In the case of Huntington’s, autophagy may be able to help clear the accumulation of misfolded proteins. Indeed, in cultured cells, seven of the eight autophagy inducers decreased the accumulation of expanded polyglutamine—the product of the infamously toxic CAG repeats found in Huntington’s patients.
After identifying the eight compounds through a series of image-based screens, which involved techniques to measure autophagical characteristics such as growth and relied on green fluorescent protein and other markers, the researchers analyzed their pathways to see whether they were identical to that of the apoptotic rapamycin. This drug leads to autophagy by targeting an enzyme inhibiting signals for cell cycle progression, cell growth, and proliferation. Yet the only commonality the eight compounds shared with rapamycin was their ability to induce the autophagical process; none of them followed rapamycin’s pathway.
True regulators of autophagy will be able to induce the digestion of misfolded proteins in neurodegenerative disorders, said Yuan. One of the identified regulators, trifluoperazine, is effective in the symptomatic relief of chorea, especially in Huntington’s patients. Since seven of the eight compounds already have the FDA’s approval for other uses, Yuan said, researchers are eager to study them further and determine their treatment requirements for misfolded-protein removal.
“What you need to do is to activate autophagy once in awhile,” said Yuan. “Hopefully, that’s all you have to do to clear your mind.”
