Huntington’s Therapy Found in Ancient Worms
A highly conserved mechanism in worms and humans has been discovered by researchers at Monash University that could provide a novel therapeutic approach for neurodegenerative diseases such as Huntington’s and Parkinson’s. A pathway involving microRNAs (miRNAs) in the removal of toxic protein aggregates – a hallmark of neurodegenerative diseases – in the brain was discovered by a team led by Associate Professor Roger Pocock from the Monash Biomedicine Discovery Institute and colleagues from the University of Cambridge led by Professor David Rubinsztein.
MiRNAs are small non-coding RNA molecules (∼22 nucleotides) that are involved in gene expression regulation. The scientists identified that one type, miR-1, is important for regulating protein aggregates and is present at low levels in patients with a neurodegenerative disease.
The researchers discovered the mechanism through the Caenorhabditis elegans worm. The miR-1 sequence is completely conserved in worms and humans, even though 600 million years of evolution separates them. They deleted miR-1 in the worm and analysed the effect it had in a preclinical model of Huntington’s, finding that protein aggregation levels increased. The miRNA was then identified as an important factor in the removal of Huntington’s aggregates.
In addition, the researchers also demonstrated that miR-1 controlled the expression of the protein TBC-7 in worms and helps against toxic protein aggregates. This protein has been identified to play an integral role autophagy, the process of removing and recycling damaged cells. Without miR-1, Huntington’s proteins became aggregated due to TBC-7 overexpression and blockage of autophagy.
Researchers then increased the expression of miR-1 and found that it removed toxic Huntington’s protein aggregates in human cells. A molecule called interferon-b was found to upregulate the miR-1 pathway in mammalian cells, reducing TBC-7 levels and allow autophagy. The team identified interferon-b as a target that could be used to manipulate miR-1 levels.
Their discoveries led to an understanding of a novel pathway that controls aggregation-prone proteins and could possible be used as a therapeutic target in alleviating neurodegenerative diseases.
This new discovery has been patented by the researchers and now looking to translate their research with pharmaceutical companies, with the hope to test it in preclinical models for Huntington’s and Parkinson’s disease.