The death of his best friend from Parkinson’s disease led an American cardiologist to go beyond his clinical background to discover a plausible cause or one of the causes of this debilitating neurological disease. The doctor is Jonathan Sackner-Bernstein, MD, founder and CEO of Right Brain Bio, Inc.
His career path includes clinical work, leadership roles at the FDA, and entrepreneurial activity on the front lines of the fight against Parkinson’s Disease. Over many years, this physician gained a strong reputation for looking at established science and data with a unique eye.
During his meticulous research, Dr. Bernstein also discovered something that collides with the common knowledge of Parkinson’s. The disease, indeed, would not be caused by low dopamine in the brain, but by high dopamine in specific areas of the brain cells.
According to Dr. Bernstein, excess dopamine in vesicles (storage membranes of enzymes, proteins, and more) is not harmful, but the same condition located in the cytosol (watery component of cytoplasm) can be a trigger for oxidative stress, alpha synuclein accumulation, and neural death.
In this framework, the doctor might have found a potential molecule that, in laboratory models, could affect and reverse his theorized cause of Parkinson’s.
But how has Dr. Bernstein arrived at his revolutionary conclusion? I met him and asked questions that every person with Parkinson’s would like to ask.
During the interview, the doctor remarked that his conclusions don’t involve suspending the dopaminergic treatment with Levodopa, because this medication does not lead to dopamine buildup. The PD mechanism is merely biological, genetic, and internal, and occurs in the brain cells of patients, not because one takes Levodopa.
Here is what Dr. Bernstein said.
Can you briefly explain what pushed you to cultivate an interest in Parkinson’s disease?
Some years ago, my dear friend Ivan began to suffer from his Parkinson’s. He challenged me to tackle his disease, despite me having no background in neuroscience. In retrospect, it was rational despite that limitation. He recognized my ability to see trends in data that others could not see.
In accordance with your research published in The Journal of Parkinson’s Disease, you affirmed that the standard treatment for Parkinson’s, aiming to increase dopamine in the brain, could be wrong, and that a more effective treatment could be the opposite, namely, reducing dopamine in the brain. What did suggest to you this type of approach in the treatment of Parkinson’s, or rather, what was the path that led you to your revolutionary conclusion?
Back when I started on this path, I wrote about those first months of work, which is available at https://www.jsbmd.com/pd. Ivan recognized that my skills and track record as a paradigm-breaker were the key skills required to find a breakthrough – and that being a cardiologist per se would not prove to be a major impediment.
Can you tell us the main reasons, features, and pillars of your discovery?
First, allow me to summarize the steps that led me to these discoveries.
The insight that led me to believe I might be able to figure something out was the recognition that Parkinson’s can’t be as simple as a disease of dopamine deficiency. If it were, then we should see the disease fixed by treatment with dopaminergic therapies. While that happened initially for Ivan, that benefit did not last.
Continuing with a First Principles analysis, the next step was to find the foundational papers and translate them from German. Once I did, I realized that these studies that established today’s standard of care – published in the 1960s – used state-of-the art-scientific methods from that era.
When I looked at these data based on the advances in knowledge since the mid-1960s, it was evident that the field had pursued the wrong approach. Those papers proved that tissue levels of dopamine were low. We know now that the measure of dopamine that dictates health vs. disease is the amount inside the dopaminergic neurons, and specifically the distribution between the vesicles — where it should be — and the cytosol — where dopamine breaks down into toxic metabolites that lead to dopaminergic neuron dysfunction and death.
Next, I looked for studies that measured or calculated the amount of dopamine within these neurons, but there were no such studies published. I figured out how to calculate these levels and learned — as reported in 2021 in the Journal of Parkinson’s Disease — that the cytosolic levels were extremely high in brains from people who had died with Parkinson’s disease (and not because of treatments they were receiving).
With that, I looked for a drug that I could use to reverse the abnormality of excess intracellular (and specifically cytosolic) dopamine. I wanted to repurpose a drug because I was only focused on helping Ivan, my buddy. And I found it – FDA-approved in 1979 when Merck developed it for the treatment of a rare cancer complication. I had to figure out how to use the drug. And at the same time, learn enough to see if I could be confident that using the drug wouldn’t worsen the disease.
I did not do this in time for Ivan, but the laboratory/preclinical data supporting this approach are very strong. Now we need to test the approach in people, which I’ve already discussed with the FDA.
There are key differences from the many approaches claimed to be a potential cure. I hesitate to think of any treatment of a chronic disease as a cure. Cures are generally possible for infections. But the data suggest our approach could stop or even reverse disease progression which would have massive importance for people with the disease and for public health. Further, we are pursuing this therapy with much stronger data than usual, which typically only show an association. We have data showing that our drug (RB-190) reverses disease pathology in 9 standard laboratory models of Parkinson’s. This means RB- 190 appears to address the cause of the disease.
Has your proposed dopaminergic reduction in Parkinson’s been applied, currently or in the past? If yes, what were the results? Can you mention case studies in this sense?
There are no clinical data using this approach for Parkinson’s disease.
Is dopamine really toxic to the brain cells? Can you explain the mechanism of this toxicity?
When there is excess dopamine in the vesicles, there is no problem. Dopamine does not break down into its metabolites when stored in the vesicles. But when it is free in the cytosol, these metabolites are formed and are highly toxic. Excess cytosolic dopamine is shown in laboratory models to increase oxidative stress, cause alpha-synuclein aggregation (in its toxic form), produce lysosomal dysfunction, trigger inflammation, interfere with mitochondrial function, and cause cell loss (via apoptosis). The metabolites that cause the toxicity are referred to as quinone and aldehyde forms.
This is distinct from what was a concern in the past about levodopa therapy. I would be grateful if your story emphasized that these toxicities are not manifestations shown with levodopa – I would not want a reader to infer or conclude that our perspectives mean they should reduce or stop their dopaminergic therapy. I am happy to discuss this in more detail but it is complicated biology and pharmacology.
As a person affected by Parkinson’s, autoimmune thyroiditis, and bipolar disorder, I recently discovered that an excess of dopamine in the brain can trigger bipolar episodes. Is there a link between high dopamine in bipolar and Parkinson’s disease?
There is a literature that focuses on potential relationships between dopamine and psychiatric conditions, but that is not my area of expertise.
Is your theory related to any Parkinson’s or only a particular phenotype caused by excitatory dopaminergic processes as seen in bipolar disorder?
The preclinical data include models that recreate DJ-1, LRRK2 and PARKIN mutations, in addition to models thought to replicate sporadic disease. I believe that RB-190 will primarily work on motor dysfunction, but it could do more.
How would you treat a patient like me, who is affected by concurrent conditions that seem linked?
I’m sorry, but I am not a neurologist and do not actively practice medicine. Therefore, I cannot usefully answer this question.
Are there additional details you want to share with the Parkinson’s community?
Please ask your reader to read my blog to keep up with our progress.
Photocredit: Audrey Bernstein
