Changes in the blood-brain barrier may explain how Parkinson’s disease progresses

parkinson patient
Genomic sequencing is being used in a new study to offer insight into the mechanisms underlying Parkinson’s disease development.
  • According to a clinical investigation, people with Parkinson’s disease have abnormalities in their blood-brain barrier.
  • This could impair the body’s capacity to filter dangerous molecules from the brain while allowing beneficial ones like glucose to enter.
  • This discovery could lead to the development of a pharmacological target for Parkinson’s disease in the future, as well as a method for evaluating the efficacy of medications in clinical trials.

Parkinson’s disease is a neurodegenerative disease that causes tremors and mobility issues. According to the Parkinson’s Foundation, it affects over 1 million people in the United States.

Parkinson’s disease has several stages because it is a progressive disease. Many researchers are looking on biomarkers that could help determine disease progression in people with Parkinson’s disease, which are generally defined by varied symptoms.

microRNA sequencing reveals genetic pathways

According to a new study published in the journal Neurology Genetics, professionals could utilize the expression of specific microRNAs in the cerebrospinal fluid of people with Parkinson’s disease not only to track disease development but also to see if a new Parkinson’s disease therapy is effective.

MicroRNAs are RNA sequences that govern the expression of messenger RNAs (mRNAs). These are used by the body to convert genetic code into proteins that the cell requires to function.

The discovery was made during a phase 2 trial that was aimed at figuring out how the leukemia treatment nilotinib could slow the advancement of motor and non-motor symptoms in Parkinson’s disease.

Dr. Charbel Moussa, Ph.D., the scientific and clinical research director of the Georgetown University Medical Center’s Translational Neurotherapeutics Program in Washington, D.C., is the senior author of both articles.

In an interview with Medical News Today, Dr. Moussa explained why his team looked at microRNAs in the cerebrospinal fluid to better understand how the medicine worked.

“This study shows that you can go to the microRNAs, which are the most stable chemicals in the cerebral spinal fluid, [to work out which genes are being expressed there].”

“And because you can detect microRNAs, then these microRNAs can be benchmarked as biomarkers of disease — not only what happens longitudinally in Parkinson’s disease, and other new diseases, but also [it] can be used as a marker of drug response.”

– Dr. Charbel Moussa, Ph.D.

Techniques

The researchers gathered 75 people with moderately severe Parkinson’s disease who had been stabilized by existing drugs.

Participants were given a single dosage of either a placebo or 150 mg, 200 mg, 300 mg, or 400 mg of nilotinib. The researchers then took a sample of their cerebral fluid and used whole-genome microRNA sequencing to evaluate it. This approach can assist scientists in determining which genes are expressed in the area.

Following a single dose of nilotinib, the researchers discovered no alterations in gene expression.

The individuals were subsequently rerandomized to receive the placebo, 150 mg, or 300 mg of nilotinib daily for 12 months. Following that, the team gathered and studied their cerebrospinal fluid once more.

After 3 months, the researchers rerandomized 63 of the subjects to receive 150 mg or 300 mg of nilotinib for another 12 months.

The 300-mg dose of the medication was shown to be safe and effective in halting motor and non-motor decline in the subjects after 27 months. The findings of this study were released earlier this year.

Changes in genetic expression revealed

The findings from whole-genome microRNA sequencing of the cerebrospinal fluid of the 75 participants before and after the first 12 months of treatment with nilotinib or the placebo are reported in the study’s most recent publication.

The scientists noticed significant changes in microRNAs that govern genes and pathways that control the development of the blood-brain barrier, the clearance of injured cells, and the formation of new blood vessels over the course of a year.

According to the study’s authors, this shows a mechanism that underpins Parkinson’s disease progression.

They determined that a 300-mg dose of nilotinib corrected these effects by inactivating DDR1, a protein that impacts the blood-brain barrier’s capacity to function properly. The usual flow of chemicals in and out of the brain filter resumed when nilotinib inhibited DDR1, and inflammation decreased to the point where dopamine was generated again.

Dr. Moussa explained, “Not only does nilotinib flip on the brain’s garbage disposal system to eliminate bad toxic proteins, but it appears to also repair the blood-brain barrier to allow this toxic waste to leave the brain and to allow nutrients in,” 

“Parkinson’s disease is generally believed to involve mitochondrial or energy deficits that can be caused by environmental toxins or by toxic protein accumulation; it has never been identified as a vascular disease.”

– Dr. Charbel Moussa, Ph.D.

Dr. Donald Grosset, the clinical director of the UK Parkinson’s Excellence Network, told MNT: “At the relatively advanced stage studied here, there could be a multitude of other reasons why these RNAs are altered. For example, rather than being the major drivers of Parkinson’s disease progression, the changes could highlight the disease’s secondary effects.”

 “Despite some doubts regarding the study’s methodology, investigating nilotinib’s role as a potential neuroprotective is incredibly significant. Overall, this study is adding significantly to our understanding about cerebrospinal fluid biomarker changes, especially relating to this type of treatment. I welcome this study’s initial findings, but much more research and clarity [are] needed in this critical area.” He added.