Neurons Under (Astrocytic) Attack

Scientists have been aware for more than a decade that astrocytes play a key role in the pathology of amyotrophic lateral sclerosis (ALS). Exactly how they contribute to neuronal death – a key feature of the condition – has remained a mystery. Many have focused on the catalog of molecules that astrocytes produce and exchange with neuronal cells. Now, a paper published in EBioMedicine describes a pathway for this process – at least in ALS patients carrying a specific genetic mutation (1)

“The problem has always been that we don’t know how astrocytes kill neurons in ALS,” says Laura Ferraiuolo, Associate Professor in Translational Neurobiology at the University of Sheffield, and one of the senior authors of the paper. Using both microarray and cellular analysis, her group has been identifying novel molecules involved in neuronal development. “We discovered that astrocytes secrete microRNAs (miRNAs), which regulate the expression of neuronal proteins that are important for axonal growth and the regulation of neuronal projections,” she says.

A major disease mechanism of ALS is synaptic loss, resulting in neuronal death (2). This led the team to consider a hypothesis: could dysregulation of these miRNAs be a major driver of this component of ALS pathology? A review of the medical literature revealed an interesting subpopulation of patients – those with mutations in a gene called C9orf72, which is found in 40 percent of familial and 8 percent of sporadic cases of ALS (3). “We found that ALS astrocytes from patients carrying a mutation in this gene secreted lower levels of miRNAs, thus causing a defect in neuronal axonal and neurite growth,” says Ferraiuolo. For the researchers, this avenue is ripe for exploration. “By demonstrating that astrocytes regulate some aspects of neuronal function through miRNAs, we’ve highlighted the potential that this class of molecules might be manipulated for therapeutic purposes,” says Ferraiuolo.

And the approach could have broad implications. “Manipulating the cross-talk between astrocytes and neurons or astrocytic function through miRNAs is applicable to a number of conditions,” explains Ferraiuolo. “In particular, the idea that we can support axonal growth via miRNAs is extremely relevant to Alzheimer’s, where synaptic loss is the main disease mechanism.”

But for now, the focus is solely on developing a suitable delivery mechanism. “We’re testing the idea that we can deliver miRNA-494 - a specific RNA we identified as a culprit of axonal degeneration -  using a gene therapy approach,” says Ferraiuolo. “There are of course several challenges related to safety and specificity that will have to be overcome. miRNAs, in particular, have several targets, so specificity will be the main challenge. We’re also working on several fronts to develop new therapeutic targets that could be applied as part of combination therapies.”