Researchers at The Scripps Research Institute have identified a possible cause of Parkinson’s disease, a finding that could lead to therapies to treat or prevent the disease.

The findings, published in the journal Molecular and Cellular Biology, draws a connection between the enzyme parkin and both cell survival and cell death pathways. The researchers made the connection by following the chain of reactions inside the specific dopamine-secreting neurons affected in Parkinson’s.

The discovery may point to a new “neuroprotective” strategy that involves reducing destruction of cell survival proteins in neurons, improving the neurons’ resistance to cellular and oxidative stresses. Prior to the discovery, it was unclear how cellular stress caused the neurons affected in Parkinson’s to die.

“We now have a good model for how parkin loss can lead to the deaths of neurons under stress,” says Steven Reed, senior author of the study and professor at The Scripps Research Institute. “This also suggests a therapeutic strategy that might work against Parkinson’s and other neurodegenerative diseases.”

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s, affecting more than seven million people around the globe. Approximately 10 percent to 15 percent of people with the disease develop symptoms early in life, around 40 years old, because of inherited mutations in a subset of genes that include the gene coding for the parkin protein.

Parkin, a ubiquitin ligase, attaches a ‘ready for destruction’ label on a subgroup of proteins inside the cell. In so doing, it serves a housekeeping function to maintain appropriate levels of a variety of proteins within cells. The research team, led by Reed, identified one of parkin’s targets as Fbw7, already known to be a regulator of cell survival in non-neuronal cells. In fact, Fbw7, itself a ubiquitin ligase, tags the cell survival protein Mcl-1, or myeloid leukemia cell differentiation protein, for destruction. Without appropriate destruction of Mcl-1, cells are resistant to programmed cell death, or apoptosis, leading to leukemia if the altered Fbw7 pathway is activated in B cells.

The research team believes it can now explain why mutations in parkin ultimately cause neuronal cell death when neurons are environmentally stressed, leading to Parkinson’s disease. Mutated parkin tags less Fbw7, decreasing the probability it will be degraded. With more Fbw7 around, a greater number of destruction flags are placed on its target, Mcl-1. Less of that cell survival protein leaves neurons more vulnerable to cellular stress and they die.

“If we can find a way to inhibit Fbw7 in a way that specifically raises Mcl-1 levels, we might be able to prevent the progressive neuronal loss that’s seen not only in Parkinson’s but also in other major neurological diseases, such as Huntington’s disease and ALS,” says Reed.

Finding an Mcl-1-boosting compound, he said, is now a major focus of the laboratory’s work. The caveat, of course, is that the boost be restricted to neurons and not affect B cells. As a promoter of cell survival, Mcl-1 plays a role in promoting certain cancers.