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Drosophila Study Links MicroRNA to Aging, Neurodegeneration

NEW YORK (GenomeWeb News) – A microRNA called miR-34 is at the heart of a network with ties to both aging and brain maintenance in the fruit fly model organism, according to a new Nature study by University of Pennsylvania researchers.

"[T]he conserved miRNA miR-34 regulates age-associated events and long-term brain integrity in Drosophila," University of Pennsylvania biologist Nancy Bonini, the study's senior author, and colleagues wrote, "providing a molecular link between aging and neurodegeneration."

As they reported online today, Bonini and her colleagues used Drosophila arrays to profile microRNAs and track gene expression in brain samples from young, middle-aged, and old fruit flies, looking for patterns that correspond to age and neurodegeneration-related processes. The hunt led them to miR-34, a miRNA that's switched on in adult flies and shows enhanced expression with age.

In the absence of this miRNA, investigators saw signs of accelerated aging and neurodegeneration, whereas higher miR-34 levels appeared to extend fruit fly lifespan and curb age-associated declines in brain structure — patterns that appear to reflect miR-34's role in keeping developmental genes silent in adulthood.

Several studies have illustrated the importance of miRNAs in regulating nervous system-related pathways as well as pathways relevant to development and aging, researchers explained. Even so, specific miRNAs involved in aging and brain maintenance are not well established.

From their preliminary experiments, the University of Pennsylvania researchers found that fruit flies with mutations in a miRNA-processing gene called loquacious were prone to premature aging and brain deterioration, hinting that miRNA-mediated pathways influence these processes.

To look at this in more detail, the team dissected brain samples from three-, 30-, and 60-day-old fruit flies from the same genetic background and used Exiqon Drosophila mercury LNA arrays to look at miRNA patterns in flies of different ages.

From pooled brain samples representing 200 to 300 fruit flies per time point, researchers found 29 miRNAs that were expressed in the adult Drosophila brain. Just one of these, miR-34, exhibited enhanced expression in older flies, though the miR-34 isoform that was expressed seemed to shift with age.

Through a series of molecular biology experiments, the team illustrated that amped up miR-34 expression seems to protect the brain and postpone aging. In fruit flies lacking miR-34, for instance, adult flies experienced rapid aging, brain deterioration, and a dramatic drop in viability at a relatively young age.

Follow-up experiments suggest that the aging and neurodegeneration seen in the flies lacking miR-34 was a consequence of unchecked expression of Eip74EF — a developmentally important transcription factor that's normally silenced by miR-34 in adult flies.

"Our studies indicate that miRNA-dependent pathways may have an impact on adult-onset, age-associated events by silencing developmental genes that later have a deleterious influence on adult life cycle and disease," the study authors noted, "and highlight fly miR-34 as a key miRNA with a role in this process."

Though researchers did not directly explore miR-34 patterns in human cells, they noted that highly conserved miR-34 orthologues have been implicated in aging and age-related disease in humans, other mammals and Caenorhabditis elegans worms, making it a promising candidate for future study.

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