Small RNA molecules may explain a hallmark of ALS

Doing the ALS Ice Bucket Challenge: a young boy dumps a pail of ice water over his head to promote awareness of amyotrophic lateral sclerosis or ALS

In the summer of 2015, a year after millions of people dumped buckets of ice water over their heads to promote awareness of amyotrophic lateral sclerosis or ALS, Zachary Hawley made the decision to join a lab at Western University focused on understanding the cellular biology of ALS. Nearly five years later, Hawley is the lead author on a recent study published in Brain Research that might explain the molecular origins of the disease.

ALS is a progressive neurodegenerative disease caused by the death of motor neurons – long and stringy brain cells that control some of our most basic operations, such as the ability to breathe, walk, speak or swallow. Perhaps no statistic to do with ALS is more telling than that the life expectancy of a person with the disease ranges from 2-5 years after diagnosis. One of its major hallmarks is the formation of sticky, microscopic aggregates caused by changes in the abundance of specific proteins, called intermediate filaments. These proteins are needed to maintain the structure and integrity of motor neurons.

“The question to us became why do we see these changes in intermediate filaments such that they’re pooling,” said Hawley, referring to the aggregation of intermediate filaments that occurs in ALS. “And that’s a critical point because intermediate filaments are as important to a neuron as the skeleton is to a human being – they provide that nice structure so that neurons can function normally and send signals.”

The study found that two microRNAs – small genetic molecules that control the amount of intermediate filament produced by motor neurons – are reduced within the spinal cord of ALS patients. This triggers a chain of events that leads these proteins to pool within motor neurons, eventually causing them to lose their strand-like structures and die.

Based on these findings, the research team suggests that restoring normal levels of these microRNAs (called miR-105 and miR-9) could slow down or reverse the progression of ALS by preventing intermediate filaments from pooling within motor neurons. Such an intervention could have life-altering consequences for ALS patients, as the only drugs currently approved for ALS treatment show minimal health benefits. However, Hawley believes there is work still to be done before the development of microRNA-based clinical interventions can occur.

“MicroRNAs are a relatively new field of study in the context of ALS so we still know very little about them,” said Hawley. “The problem is that we still don’t understand why these microRNAs are dysregulated. We know they’re causing a lot of issues, but now we need to figure out why they’re causing these issues, or why they’re so dysregulated in ALS patients.”

Now in the final year of his PhD, Hawley is soon joining the lab of Kevin Eggan at Harvard University as a visiting scholar, where he hopes to gain a better understanding of the causes of microRNA dysregulation in ALS. “Our models are very limited,” he said. “So I’m going there to test some of my hypotheses in actual motor neurons from ALS patients to see if what I’m thinking is actually correct.”

Hawley says he is still interested in studying neurodegenerative diseases like ALS after completing his doctoral studies. The research team hopes to follow up this study by identifying the specific features that drive microRNA dysregulation and protein aggregation in the disorder.

Original Research Article: Hawley, Z. C. E., Campos-Melo, D., & Strong, M. J. (2019). MiR-105 and miR-9 regulate the mRNA stability of neuronal intermediate filaments. Implications for the pathogenesis of amyotrophic lateral sclerosis (ALS). Brain Research, 1706, 93–100. https://doi.org/10.1016/J.BRAINRES.2018.10.032