miR-1 loss leads to improved motility in a worm model for Huntington’s Disease
Caenorhabditis elegans is an established model for age-associated neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, allowing the study of toxic protein aggregation and age-related motility decline. A team of researchers led by Adam Antebi at the Max Planck Institute for Biology of Ageing has now been able to reduce protein aggregation by removing a specific microRNA called miR-1 in different C. elegans neurodegenerative disease models. They were able to show that this microRNA plays a role in the function of lysosomes - the "stomach of the cell" - and also influences muscle function during ageing.
MicroRNAs are short RNAs that regulate gene-expression. The Cologne scientists have now investigated a specific microRNA, called miR-1. This microRNA is enriched in muscle tissues in worms and in mammals. The researchers knew from previous studies that miR-1 expression changes with ageing.
"We were interested in the role of miR-1 in the ageing process. However, when we removed miR-1 in C. elegans, we didn't see much of an effect. Therefore, we looked at a C. elegans neurodegenerative disease model that simulates Huntington's disease by triggering protein aggregates in cells," explains Kazuto Kawamura, one of the study's first authors.
When the researchers deleted miR-1 in the worms, they observed less protein aggregation in this neurodegenerative disease model compared to worms with normal miR-1 expression. Because miR-1 is found in muscles, the researchers studied the worms' motility. "The worms without miR-1 were significantly more mobile than their counterparts. Since the decline in muscle function is a typical hallmark of ageing, this was very interesting to us," explains Adam Antebi. "We therefore looked more closely at which genes are regulated by miR-1."
Reduction of protein aggregates
The researchers found v-ATPases as likely targets of miR-1. v-ATPases are located on lysosomes that act as the digestive system of cells and also degrade protein aggregates. "Thanks to a great team from my lab, consisting of Isabelle Schiffer, Birgit Gerisch, Kazuto Kawamura, Raymond Laboy and Orsolya Symmons, we were able to show a direct link between the microRNA and the lysosomes. This might explain why we find fewer protein aggregates in these worms," Antebi said. "The lysosome is also involved in many signaling pathways in the cell, which, for example, control cell growth or cell division. In the future, it will be interesting to investigate whether miR-1 also influences these processes."
Isabelle Schiffer, Birgit Gerisch, Kazuto Kawamura, Raymond Laboy, Jennifer Hewitt, Martin Sebastian Denzel, Marcelo A Mori, Siva Vanapalli, Yidong Shen, Orsolya Symmons, Adam Antebi
miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact proteotoxicity and muscle function during ageing
eLife July 2021
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