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New research uses genomic sequencing to shed light on the mechanisms behind Parkinson’s disease progression.
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  • A clinical study shows that people with Parkinson’s disease experience changes in their blood-brain barrier.
  • This could affect the body’s ability to filter harmful molecules away from the brain and let helpful molecules, such as glucose, into the brain.
  • This discovery could provide a potential drug target for Parkinson’s disease in the future and offer a way to assess the effectiveness of drugs in trials.

Parkinson’s disease is a progressive neurological condition that causes tremors and mobility problems. It currently affects nearly 1 million people in the United States, according to the Parkinson’s Foundation.

As Parkinson’s disease is progressive, there are a number of stages to the condition. These are normally characterized by different symptoms, but many researchers are investigating biomarkers that could help determine disease progression in people with Parkinson’s disease.

Now, a study in the journal Neurology Genetics suggests that experts could use the expression of certain microRNAs in the cerebrospinal fluid of people with Parkinson’s disease not only to follow disease progression but also to determine if a new Parkinson’s disease drug works.

MicroRNAs are short sequences of RNA that regulate the expression of mRNAs. The body uses these to translate the genetic code into proteins that the cell needs to function.

The discovery came in a phase 2 trial designed to uncover the mechanism behind a previous finding: that the leukemia drug nilotinib could halt the progression of motor- and non-motor-related symptoms in Parkinson’s disease.

The senior author of both papers is 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.

Dr. Moussa told Medical News Today in an interview why his team looked at microRNAs in the cerebrospinal fluid to get a better picture of how the drug was working.

“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.

The researchers recruited 75 people with moderately severe Parkinson’s disease that existing drugs had stabilized.

The participants received either a single dose of a placebo or 150 milligrams (mg), 200 mg, 300 mg, or 400 mg of nilotinib. The researchers then collected their cerebrospinal fluid and analyzed it using whole-genome microRNA sequencing. This method can help scientists deduce which genes are being expressed there.

The researchers found no changes in the expression of genes following a single dose of nilotinib.

They then rerandomized the participants to receive either the placebo or 150 mg or 300 mg of nilotinib daily for 12 months. After this, the team collected and analyzed their cerebrospinal fluid again.

Around 3 months after this, the team again rerandomized 63 of the participants to receive either 150 mg or 300 mg of nilotinib for a further 12 months.

After 27 months, the 300-mg dose of the drug was shown to be safe and effective at stopping motor and non-motor decline in the participants. The results of this research became available earlier this year.

The latest publication from this study reports 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.

Over the 12-month period, the scientists observed significant alterations in microRNAs that control genes and pathways that regulate the production of the blood-brain barrier, the removal of damaged cells, and the formation of new blood vessels.

The study authors argue that this reveals a mechanism that underlies the progression of Parkinson’s disease.

Specifically, they discovered that the 300-mg dose of nilotinib reversed these effects by inactivating a protein called DDR1 that affects the ability of the blood-brain barrier to function correctly. On the inhibition of DDR1 by nilotinib, the normal transportation of molecules in and out of the brain filter resumed, and inflammation declined to the point that dopamine was being produced again.

“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,” Dr. Moussa explained.

“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, the changes could signal the secondary effects of having Parkinson’s, rather than being the primary drivers for the disease’s progression.”

He added: “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.”