New Northwestern Medicine® research is believed to have uncovered a novel therapeutic target for the number one genetic killer of toddlers in the developed world.
Spinal muscular atrophy (SMA), a “relatively common rare disorder” affecting 1 in 6,000 babies, is caused by a mutated gene affecting motor neurons. Although the genetic cause of the disease is well understood, there exists no cure.
“What we’ve found is a new signaling pathway,” said Yong-Chao Ma, PhD, assistant professor in pediatrics, neurology, and physiology, and Ann Marie and Francis Klocke, MD, Research Scholar. “This enzyme, cyclin-dependent kinase 5, has never before been implicated in the development of SMA, and we have found that its activity is increased only under disease conditions and only in the motor neurons that degenerate in the disease.”
SMA’s impact on motor neurons affects the voluntary muscles used for activities such as crawling, walking, head control, and swallowing. In adults, the degeneration of motor neurons results in ALS, or Lou Gehrig's disease.
“With this new information, we think we may have found a biomarker, which would help diagnose this disease and then allow for inhibition of the pathway as a new treatment strategy,” said Ma, a member of the Ann & Robert H. Lurie Children's Hospital of Chicago Research Center and the Center for Genetic Medicine.
To test this hypothesis, researchers in his lab have begun to apply inhibitors to the pathway to see if they stop SMA progression.
“We are seeing some very promising data,” Ma said. “Right now, there is no early detection of SMA beyond genetic analysis, and what we think we have discovered is a novel mechanism and treatment target.”
Beyond the cells involved in SMA, Ma’s lab is also exploring the dopaminergic neurons whose deterioration leads to Parkinson’s disease (PD).
“These two cell types are related in our view because the mechanism that regulates their development, the transcription factor, is shared,” Ma said.
Researchers in Ma’s lab believe they have identified a new mechanism that can help explain age-dependent, stress-induced dopaminergic neuron degeneration. Based on the discovery of this mechanism, investigators are hoping to develop the potential for new treatments in the fight against Parkinson’s.
“These studies are relatively new and we will work with D. James Surmeier’s lab to develop them further,” Ma said.
How stress regulates dopaminergic neurons is unknown, but Ma began his most-recent work by investigating the role of the stress mediator sirtuin and its role in dopaminergic neuron development and degeneration.
“This has led us to the identification of some novel transcription factors that regulate dopaminergic fate, and we are further investigating the roles of these factors,” he said.
One shared property between SMA and Parkinson’s disease is the selective degeneration that occurs in both. Although the genetic mutation in SMA happens in all cell types, only motor neurons deteriorate and die because of it. In familial PD, all cells carry the same genetic mutations and yet only dopaminergic neurons degenerate.
“In either disease, as these cells start to degenerate, we see a shared mechanism,” Ma said. “I think these findings really open up new avenues for future research because the signaling pathways identified have never been implicated before.”
Ma’s SMA research is funded by Families of SMA and the Searle Leadership Fund in the Life Sciences. His work on PD is funded by the Whitehall Foundation and the Brain Research Foundation.