COMMON MUTATION IN PARKINSON'S DISEASE INCREASES CELL CALCIUM, MAY CAUSE BRAIN CELL DEATH
Johns Hopkins Medicine researchers have mapped out the cellular pathway that connects the most common genetic mutation associated with Parkinson's disease to brain cell death. In a new study, they show that the mutation initiates a biological pathway that could target brain cells most susceptible to the patterns of cell death leading to Parkinson's disease symptoms.
"This deep dive into the molecular players in Parkinson's disease may provide some answers to its onset and progression," says Valina Dawson, Ph.D., professor of neurology at the Johns Hopkins University School of Medicine, and director of both the neuroregeneration and stem cell programs at the medical school's Institute for Cell Engineering.
The study, published Oct. 1, 2020, in the journal Cell Stem Cell, revealed that a mutation in the leucine-rich repeat kinase 2 (LRRK2) gene shifts the balance of protein production within brain cells, allowing calcium to accumulate inside them. Though mutations in LRRK2 are the most common indicators of inherited Parkinson's disease, their functions within cells are not well understood.
Dawson and her research team learned that a specific mutation within the LRRK2 gene, called Gly2019Ser, or G2019S, produces a protein that becomes more active than normal. They found that this increased activity changes how ribosomes, the protein-making factories of the cell, select which RNA molecules are used to make other proteins. Ribosomes affected by the mutated LRRK2 protein prefer some RNAs with more complex structures than other simple RNAs.
"This preference causes major problems down the line, because it may shift the levels of proteins whose precise regulation is essential for neurons to function and survive," explains Dawson.
Among the consequences, says Dawson, is the regulation of many cell structures that are responsible for maintaining healthy levels of calcium. One such affected structure is the voltage-gated calcium ion channel, a portal crucial for processing and sending biochemical messages across the brain. Previous studies established that too much calcium in a brain cell can cause it to die. Excess calcium also has been linked as a contributing factor to Alzheimer's disease.
"Mapping out this progression of events is an important advancement in understanding the disease and provides more information on how Parkinson's disease may initially arise," says Dawson.
The research team hopes its findings provide opportunities to create new therapies for Parkinson's disease. "Defining each step in the pathway linking the LRRK2 mutation and brain cell death represents a potential target for drug interaction," says Dawson.
BETTER REPAIRED NERVE INSULATION MAY LEAD TO NEW MULTIPLE SCLEROSIS TREATMENTS
Vanessa McMains, Ph.D.
In a new study using mice, Johns Hopkins Medicine researchers have found a better way than natural healing to repair damaged insulation surrounding nerve cells. Normally, the natural healing process adds bumps to the surface of the protective fatty sheath, known as myelin, each time it's repaired. Over time and after cumulative damage, the myelin ultimately becomes too misshapen to wrap cleanly around the nerve, causing it to lose function.
This happens in multiple sclerosis (MS), a disorder in which the body's immune system mistakenly attacks the myelin around nerves, shutting them down and causing communication problems between the brain and the rest of the body.
In their study published on Oct. 2, 2020, in Science Advances, the researchers say that using certain drugs may prevent relapsing-remitting MS, the intermittent form of the disorder, from becoming progressive MS -- a chronic form of the condition in which the myelin can no longer repair itself.
"Suppressing the immune system has worked to treat relapsing-remitting MS, but it doesn't protect from the eventual advancement to progressive MS, for which there aren't any good treatments on the market," says Norman Haughey, Ph.D., professor of neurology at the Johns Hopkins University School of Medicine. "We think these findings are a big step toward improving the quality and composition of myelin following a flare-up."
In earlier work by Haughey's team, the researchers looked at the composition of the myelin surrounding nerves found near injured brain tissue taken from deceased people with MS. Myelin is made mostly from hundreds of types of fat molecules and proteins. The researchers saw that myelin around nerves near injury sites looked misshapen compared with that of other nerves, along with having much higher levels of ceramide -- a particular type of fat molecule -- and lower levels of another fat molecule called sulfatide.
Having the correct amount of ceramide is especially important because this fat regulates the curvature of myelin -- too much ceramide and it can't wrap tightly around the nerve, creating "bumps" in the myelin.
In the new study, the researchers fed the drug cuprizone to mice for 26 days to damage the myelin on their nerve cells. The myelin repaired itself, but looked it bumpy and wrapped poorly around the nerve because of the excess ceramide. In a series of experiments, the researchers found that brain inflammation activates the enzyme, neutral sphingomyelinase-2, which produces ceramide.
Working with an expert drug development team led by Barbara Slusher, Ph.D., M.A.S., professor of neurology at the Johns Hopkins University School of Medicine, the researchers identified the small molecular size drug, cambinol, which blocks neutral sphingomyelinase-2 from working. They theorized that this would prevent excess ceramide from being made and incorporated into regenerated myelin after an injury.
After nearly a month of feeding their mice cuprizone to cause myelin damage, the researchers injected them with cambinol. When the myelin grew back this time, it wrapped tightly around the neurons and looked like it did before the damage.
The researchers say this intervention did not completely restore the fat composition of myelin, but it appeared to increase the stability of the myelin, which likely would better protect the underlying neurons.
The team needs to determine if there are impacts from other abnormal fat levels in the repaired myelin even with the prevention of excess ceramide buildup. Also, the researchers need to confirm that the myelin -- after being in its correct shape and structure -- functions as it should and is more stable over long periods of time.
Once this is done, the team hopes to develop small molecular-size inhibitors of neutral sphingomyelinase-2 for eventual use in human trials.
Postdoctoral fellow Seung-Wan Yoo, Ph.D., M.S., is the lead author of this study.