LA JOLLA, Calif.—Alzheimer’s disease, Parkinson’s disease and autism are terms frequently lumped together under the label of neurodegenerative diseases, but a recent study has discovered that these conditions might have something else in common: the effects of a transcription factor known as MEF2. Researchers from the Sanford-Burnham Medical Research Institute have discovered that a chemical “switch,” which turns off the signals that promote neuron production and survival, is abundant the brains of patients with neurodegenerative diseases, and therefore could offer a new target for treatment. The study, “S-nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death,” was published July 3 in Cell Reports.
Transcription factors in the MEF2 family have significant roles in neurogenesis, the production of brain cells, and neuronal survival, in addition to the processes of memory and learning. Mutations in this gene are associated with several neurodegenerative disorders, such as Alzheimer’s and autism.
Dr. Stuart Lipton, director of the Neuroscience and Aging Research Center at Sanford-Burnham—as well as a professor there—and senior author of the study, and his collaborators laid the groundwork for this latest discovery 20 years ago with another paper. In it, they described the process of nitric oxide (NO)-protein modification, also known as S-nitrosylation. While this is a normal signaling process in a healthy system, it can become aberrant and contribute to disease pathogenesis. That’s what may be happening in the case of MEF2, says Lipton.
“We have shown that when nitric oxide—a highly reactive free radical—reacts with MEF2, MEF2 can no longer bind to and activate the genes that drive neurogenesis and neuronal survival,” Lipton, who is also a practicing clinical neurologist, explained in a statement. “What’s unique here is that a single alteration to MEF2 controls two distinct events—the generation of new neurons and the survival of existing neurons.”
Fortunately, this is something that can be targeted, he adds. Using mouse cells and induced pluripotent stem cell-generated human brain cells, the team found that by preventing nitrosylation, or giving more active MEF2, brain cells could be rescued. This could offer the ability to promote the growth of new brain cells and protect existing ones, Lipton noted in a statement.
Lipton and his collaborators examined the effects of MEF2 in Parkinson’s disease in a 2013 study titled “Isogenic human iPSC Parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC-1α transcription.” In the paper’s abstract, the authors noted that “We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2C-PGC1α transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction in the pathogenesis of [Parkinson’s disease]. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1α pathway as a therapeutic target to combat [Parkinson’s disease].”
“Our laboratory had previously shown that S-nitrosylation of MEF2 controlled neuronal survival in Parkinson’s disease,” said Lipton. “Now we have shown that this same reaction is more ubiquitous, occurring in other neurological conditions such as stroke and Alzheimer’s disease. While the major gene targets of MEF2 may be different in various diseases and brain areas, the remarkable new finding here is that we may be able to treat each of these neurological disorders by preventing a common S-nitrosylation modification to MEF2.”
The researchers are in pursuit of drugs that might be capable of targeting MEF2 and have already found a number of small molecules via high-throughput screening.
“We have some [molecules that block nitrosylation of MEF2], but we’re actually more excited right now by molecules that super-activate MEF2,” Lipton tells DDNews. “We don’t know if they’re removing the nitrosylation or activating MEF2 in some other way, but they do overactivate MEF2, and that can rescue the cells.”
