
A Northwestern Medicine study has revealed a key mechanism underlying the development of motor neuron diseases, offering new insights into potential treatment options, according to a study published in the Journal of Neuroscience.
Investigators discovered that a genetic mutation in the RNA-binding protein Ataxin-2 (ATXN2) disrupts the stability of microtubules — central components of the cytoskeleton in motor neurons — leading to impaired neuron growth and function. The findings may help inform the treatment of amyotrophic lateral sclerosis (ALS), which progressively destroys motor neurons and leads to muscle weakness and paralysis.
The study, conducted using a mixed-sex population of fruit flies, sheds light on how expansions in ATXN2’s polyglutamine (polyQ) repeats contribute to ALS risk. ALS has long been associated with protein mislocalization and aggregation. While ATXN2 has been known as a genetic risk, the precise biological mechanism remained elusive until now.
“We decided to model polyQ expansion in fruit flies because it takes much less time to study genetic changes compared to mammals,” said Vladimir Gelfand, PhD, the Leslie B. Arey Professor of Cell, Molecular, and Anatomical Sciences and senior author of the study.
By observing neurons in fruit flies with and without ATXN2, the research team observed that the gene regulates microtubule dynamics through its RNA-binding domain. When cells were treated with the human version of this domain, scientists were able to restore normal microtubule behavior in fruit flies, suggesting that this function is similar across species.
However, when ATXN2 carries expanded polyQ repeats, it was found to form toxic cytoplasmic aggregates that destabilize microtubules and severely impair axon outgrowth — key processes in healthy neuron development.

With no effective treatment currently available for ALS, these findings mark a step toward understanding the disease at a cellular level — and potentially developing interventions that target the root causes of motor neuron degeneration.
“Scientists still don’t know why polyQ expansion causes neurodegeneration, and this study essentially shows that the effect of it on microtubules is one of the key changes,” Gelfand said. “This is a long way from trying it in clinics, but it gives us a direction for the future.”
Sun Kim, PhD, an alumna of the Driskill Graduate Program in Life Sciences (DGP), was the first author of the study.
This research was supported by the Les Turner ALS Foundation Research Grant and the National Institute of General Medical Sciences Grant R35GM131752-06.