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Autophagy study proposes new strategy for the treatment of age-related neurodegenerative diseases



Brown University scientists say they have demonstrated a novel method of stimulating autophagy. In a study ("Nuclear Export Inhibition Enhancements HLH-30 / TFEB Activity, Autophagy and Lifespan"), published in Cell Reports the team demonstrates that the approach increases the lifespan of worms and flies and experiments in human Cells suggest that the strategy could be useful in future treatments for Alzheimer's disease, amyotrophic lateral sclerosis ( ALS) and other age-related neurodegenerative conditions.

"The transcriptional modulation of the autophagy process involves the transcription factor HLH-30 / TFEB To systematically determine the HLH-30 / TFEB regulatory network, we performed a genome-wide RNAi [RNA interference] screen in C. and found that the nuclear export protein XPO-1

/ XPO1 enhances autophagy by a significant accumulation of HLH-30 in the nucleus, which has advantages in terms of proteostasis and longevity. xpo-1 Muting requires HLH-30 and autophagy that mechanistically overlap several established longevity models Selective XPO1 inhibitors repeat the silencing-observed effect on autophagy and lifespan xpo-1 and protected ALS-affected flies from neurodegeneration ", the researchers write.

XPO1 inhibition in HeLa cells enhanced TFEB [transcription factor EB] nuclear localization, autophagy, and lysosome biogenesis without affecting the activity of mTOR [mechanistic target of rapamycin]demonstrating a conserved regulatory mechanism for HLH-30 / TFEB. Overall, our study shows that altering the nuclear export of HLH-30 / TFEB can regulate autophagy and substantiates the goal to stimulate XPO1 autophagy to prevent neurodegeneration. "

" Autophagy dysfunction exists over a range of age-related illnesses including neurodegeneration, "said Louis Lapierre, Ph.D., assistant professor of molecular biology, cell biology and biochemistry at Brown, who led the work." We and others think that, as we learn to pharmacologically influence this process, we can influence the progression of these diseases. What we have shown here is a new and conserved access point for the stimulation of autophagy. "

Autophagy involves rounding up misfolded proteins and outdated organelles within a cell into autophagosomes, which then fuse into a lysosome that breaks down these cellular macromolecules and converts into components that the cell can reuse.

Dr. Lapierre and his colleagues wanted to find out if they can increase autophagy by manipulating a transcription factor that regulates autophagic activity, so that the transcription factor activates autophagic activity Thus, Dr. Lapierre and his team have searched for genes that increase the level of autophagy transcription factor, known as TFEB, within nuclei.

Using the Nematode found Caenorhabditis elegans the screen that the expression of a pro tein called XPO1, which transports proteins from the nucleus, leads to the nuclear accumulation of the nematode version of TFEB. This accumulation was associated with an increase in autophagy markers, including increased autophagosome and autolysosomes as well as increased lysosomal biogenesis. The lifetime of the treated nematodes was also significantly increased between about 15% and 45%.

"We were able to show that blocking the transcription factor from the nucleus not only affects autophagy, but also we" Lapierre said

The next step was to see if there were any drugs that could affect the effect of gene inhibition Could mimic the screening experiment. The researchers found that selective inhibitors of nuclear export (SINE), originally developed to inhibit XPO1 in the treatment of cancer, had a similar effect, ie, increased autophagy and significantly extended the life of nematodes.

The researchers then tested SINE on a genetically engineered fruit fly that serves as a model organism for the neurodegenerative disease ALS. These experiments showed a small but significant increase in the lifespan of the treated flies. "Our data suggest that these compounds can alleviate some of the neurodegeneration in these flies," Dr. Lapierre.

As a last step, the researchers wanted to find out if the XPO1 inhibition had similar effects on autophagy in human cells in the nematodes. After treating a culture of human HeLa cells with SINE, the researchers found that Tefeb concentrations in cell nuclei as well as autophagic activity and lysosomal biogenesis increase.

"Our study shows that the regulation of intracellular partitioning of TFEB is conserved from nematodes to humans and SINE could stimulate autophagy in humans," Dr. Lapierre continues. "SINE has recently been shown in clinical trials for the safety of cancer, so there is potential for the use of SINE in other age-related diseases."

Scientists will now focus on testing these drugs in clinically relevant models of neurodegenerative diseases, but this initial research is a proof of concept for this strategy as a means of increasing autophagy and possibly treating age-related diseases, according to Dr , Lapierre


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