Ancient worm reveals way to destroy toxic cells in Huntington’s disease
Researchers from Monash Biomedicine Discovery Institute (BDI), Univeristy of Cambridge and University of Copenhagen, have identified a highly conserved mechanism in worms and humans that controls the removal of toxic protein aggregates – hallmarks of neurodegenerative diseases. Insights from their study may provide a novel therapeutic approach for diseases such as Huntington's and Parkinson's. Their findings were recently published in eLIFE.
miR-1 –A small but important molecule
MicroRNAs, short strands of genetic material, are tiny but powerful molecules that regulate many different genes simultaneously. The scientists sought to identify particular microRNAs that are important for regulating protein aggregates and homed in on miR-1, which is found in low levels in patients with neurodegenerative diseases such as Parkinson’s disease.
In their study, researchers used the tiny worm called C. elegans, since the sequence of miR-1 is 100 per cent conserved; it’s the same sequence in the C. elegans worm as in humans even though they are separated by 600 million years of evolution. Because of this, the worm can be used as a model to predict molecular mechanisms in humans.
“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,” Associate Professor Pocock from Monash University said. “This suggested miR-1 was important to remove Huntington’s aggregates.”
The researchers then showed that miR-1 helped protect against toxic protein aggregates by controlling the expression of the TBC-7 protein in worms. This protein regulates the process of autophagy, the body's way of removing and recycling damaged cells and is crucial for clearing toxic proteins from cells. Without miR-1, autophagy does not work correctly and there is an aggregation of Huntington’s proteins in the worms.
In the next phase of the study, researchers conducted an experiment, which showed that miR-1 regulates the same pathway in human cells. Expressing more miR-1 removes Huntington’s aggregates in human cells.
“It’s a novel pathway that can control these aggregation-prone proteins. As a potential means of alleviating neurodegenerative disease, it’s up there,” Associate Professor Pocock said.
Known drug upregulates the miR-1 pathway
Additional work by the researchers from University of Copenhagen and the University of Cambridge showed that when human cells are supplied with a molecule called interferon-b the miR-1 pathway is upregulated, revealing a way of manipulating it. Interferon-b is already being used to treat patients with multiple sclerosis.
“We have previously shown that interferon-beta can increase the degradation of disease-causing proteins related to Parkinson's disease. In this new study, we discovered, by chance, that interferon-beta can activate miR-1, and we even found a molecular mechanism by which the interferon-beta / miR-1 signaling pathway promotes the degradation of toxic protein accumulations. This study shows the importance of asking fundamental questions and conducting basic research for a better understanding of diseases” says Assistant Professor Patrick Ejlerskov, University of Copenhagen.
He said the studies demonstrated the fundamental importance of discovery research. “We asked a fundamental biological question to dissect a molecular mechanism that now is shown to be really important for potential therapies.”
The researchers have provisionally patented their findings and are in discussions with pharmaceutical companies about translating the research. They will further test it in preclinical models for Huntington’s and Parkinson’s disease.
This research was supported by the Australian NHMRC.