MicroRNA May Help Prevent Buildup of Toxic Proteins in Huntington’s Disease, Study Shows

MicroRNA May Help Prevent Buildup of Toxic Proteins in Huntington’s Disease, Study Shows
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A small RNA molecule known as microRNA-1, found in both worm and human cells, can promote the removal of toxic protein aggregates — hallmarks of neurodegenerative diseases — by triggering a self-cleaning process called autophagy, a study shows.

These findings may open new avenues for potential therapeutics for disorders such as Huntington’s disease.

The study, “Interferon-β-induced miR-1 alleviate toxic protein accumulation by controlling autophagy,” was published in the journal eLIFE.

Huntington’s disease is caused by a mutation in the huntingtin (HTT) gene. The mutation is known as a CAG trinucleotide repeat expansion, meaning the gene contains an excessive number of repeats of a portion of the DNA called CAG triplets, which carries instructions to produce the amino acid glutamine. Amino acids are the building blocks of proteins.

The result is an abnormal huntingtin protein that is cut into smaller toxic pieces, which clump, or aggregate, together inside nerve cells, preventing their functioning and triggering the cell’s death.

Autophagy, which literally means “self-eating,” is a key process used by our cells to maintain equilibrium: It degrades cellular components that are damaged or no longer required so they can be recycled and used in new functions.

The removal of aggregation-prone proteins can be enhanced by autophagy. As such, understanding how autophagy is controlled may aid in the development of new therapies to treat Huntington’s disease.

MicroRNAs are a special class of short RNA molecules capable of regulating the activity of multiple genes simultaneously.

The levels of a particular microRNA, called miR-1, were found to be present in lower-than-normal levels in the cerebrospinal fluid (the fluid surrounding the brain and spinal cord) of Parkinson’s disease patients, which prompted researchers to “investigate if mir-1 is required for preventing the accumulation of aggregation-prone proteins.”

Since the genetic sequence of the human miR-1 is conserved across animals — meaning it is similar between species — the team used a worm model, called Caenorhabditis elegans, that expresses the same type of mutation seen in Huntington’s disease.

“The sequence of miR-1 is 100 per cent conserved; it’s the same sequence in the Caenorhabditis elegans worm as in humans even though they are separated by 600 million years of evolution,” Roger Pocock, PhD, an associate professor at the Monash Biomedicine Discovery Institute and the study’s lead author, said in a press release.

When they removed the gene for miR-1, the worms had enhanced mutant protein aggregation and an abnormally high number of glutamine-rich repeats, a hallmark of Huntington’s. The overall levels of the protein, however, remained unchanged.

“We deleted miR-1 in the worm and looked at the effect in a preclinical model of Huntington’s and found that when you don’t have this microRNA there’s more aggregation,” Pocock said. “This suggested miR-1 was important to remove Huntington’s aggregates.”

They also found that miR-1 was important in preventing protein aggregation in a C. elegans model of Parkinson’s disease, which is characterized by the buildup of alpha-synuclein protein.

To understand how miR-1 helped protect against toxic protein aggregates, the team searched for possible targets of this microRNA molecule. Using a combination of RNA sequencing (a technique that analyzes all RNA molecules) and genetic assays, they found that a single gene, called TBC-7, appeared to be the target of miR-1.

Specifically, miR-1 helped protect against toxic protein aggregates by decreasing the levels of the TBC-7 protein in the worm. TBC-7 is a protein involved in autophagy. In other words, loss of miR-1 caused an increase in TBC-7, which consequently blocked the normal autophagy process.

“When you don’t have miR-1, autophagy doesn’t work correctly and you have aggregation of these Huntington’s proteins in worms,” Pocock said.

The researchers found that the same mechanism also occurs in humans: The human version of TBC-7, known as TBC1D15, was also regulated by miR-1 in mammalian cells.

“Expressing more miR-1 removes Huntington’s aggregates in human cells,” Pocock said.“It’s a novel pathway that can control these aggregation-prone proteins. As a potential means of alleviating neurodegenerative disease, it’s up there.”

Using a human cell line with a tagged version of the mutant huntingtin protein, the team showed that increased levels of miR-1 prevented mutant huntingtin protein aggregation.

However, this effect was lost if autophagy was blocked, once more indicating that miR-1 acts through the autophagy pathway to regulate protein aggregation.

To gain further insight into potential therapeutic targets, the team investigated how miR-1 levels could be regulated.

A small cytokine protein, called interferon-beta, was shown to increase the levels of miR-1 and decrease those of TBC1D15 in a mouse model. Adding interferon-beta to human cells resulted in the same changes and also decreased mutant huntingtin protein aggregation. However, this effect was lost if miRN-1 was inhibited.

“Our data imply that deficits in miR-1 and TBC protein function may contribute to the etiology of protein aggregation disorders and their manipulation by [interferon-beta] could provide novel therapeutic opportunities in treating these diseases,” the researchers concluded.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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