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International Parkinson and Movement Disorder Society
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Erythrocytic α-synuclein and spreading pathology in Parkinson’s disease

February 26, 2024
Prof. Tiago Outeiro interviews Dr. Jing Zhang on his most recent paper in the Movement Disorder Journal on the erythrocytic alpha synuclein and the gut microbiome. Together they discuss alpha synuclein spreading pathology and the promising future of blood biomarkers for Parkinson’s disease.
Journal CME is available until March 02, 2025 Read the article.

[00:00:05] Dr. Tiago Outeiro: Hello, and welcome to the MDS podcast. The podcast channel of the International Parkinson and Movement Disorder Society. I am Tiago Outeiro, professor at the University Medical Center Göttingen in Germany. And today I have the pleasure to interview Dr. Jing Zhang from the Department of Pathology, Zhejiang University School of Medicine and the first affiliated hospital in China.

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Dr. Zhang and his team have recently published an article in the Movement Disorders Journal entitled Erythrocytic Alpha synuclein and the Gut Microbiome, Kindling of the Gut Brain Axis in Parkinson's Disease. I find this a very interesting and overlooked topic, as we tend to always think only of alpha synuclein as a neuronal protein.

So Dr. Zhang what is the function of alpha synuclein in the blood and in particular in erythrocytes? What do we know about this?

[00:00:55] Dr. Jing Zhang: That's a very good question. The short answer is we don't know. So it has been [00:01:00] proposed by many investigators as far as the function of the alpha synuclein in the brain, but peripherally the function of the alpha synuclein is essentially unknown. We have published recently a paper in the Journal of Advanced Research showing that red cell containing alpha synuclein could potentially influence morphology of the red blood cells.

In fact, in patients with Parkinson's disease, they often show up abnormality of red blood cells and often will be associated with anemia. Yeah, so we don't know but there's many potentials for us to research.

[00:01:42] Dr. Tiago Outeiro: Yeah, absolutely, I think this is fascinating and I think it fits also within this idea that alpha synuclein may influence membrane curvature. So I think this fits perfectly and I agree. I think we need more research on this topic. So besides the blood and the brain, because the brain is the organ where we normally think of Alpha [00:02:00] synuclein are there other tissues in which we can find Alpha synuclein? 

[00:02:03] Dr. Jing Zhang: Yes, indeed besides the brain people talk a lot as far as the expression of alpha synuclein beyond the brain, what includes the gut. That's what this paper is about. And they are also expressed in the lung, kidney, and skin. People nowadays talking about using skin biopsy for Parkinson's disease diagnosis. We all know about the gut brain axis, but if you also talk about the brain and kidney axis. Brain and a lung axis. So the reason for that is people will see the expression alpha synuclein in a lung in the kidney in addition to the skin and the gut.

[00:02:45] Dr. Tiago Outeiro: Yeah, I think this is really important because we tend to be very conservative and think of only alpha synuclein in the brain, but there's a lot of alpha synuclein in other places as well. But so when we think about blood synuclein and brain synuclein, what [00:03:00] do we know about this connection? Is it reasonable to expect that the blood synuclein can tell us something about what's happening in the brain? 

[00:03:07] Dr. Jing Zhang: Right. Actually that's one of the high hypothesis we are working on the moment.

So in our research we believe that the red cell containing alpha synuclein is a fundamental source for a majority of organs, including the brain. So people talk about brain versus the body first, parkinsonism.

 What determines how the brain will develop Parkinson's versus the body developed Parkinson's first, maybe is due to how efficiently the alpha synuclein from the red cell transmits to the brain versus transmits to the gut. The things to consider is the relative amount of alpha synuclein expressed in red cells. Which is very high. Higher than what's expressed in the brain. So in that regard, it [00:04:00] can be expected that the high levels of alpha synuclein from red cell could transmit to any organ, including skin, gut, kidney, lung, and brain. If the brain brain barrier is compromised, therefore, depending on how much alpha synuclein is transmitted to each organ, that may dictate which organ gets involved for the Lewy body disease.

That's the hypothesis we're working on.

[00:04:28] Dr. Tiago Outeiro: This is really fascinating. And so now we are entering really the territory of your study. So can you please summarize the main findings of your study?

[00:04:37] Dr. Jing Zhang: Yes, I would love to. So there are several key points of our research published in the Movement Disorder recently. Number one we discovered that the alpha synuclein protein is pretty high in the gut compared to the brain.

At the same time, the mRNA that directs expression of alpha synuclein [00:05:00] is rather low, much lower in the gut compared to the brain.

So that prompted us to ask the question, where is the alpha synuclein potentially coming from? Now, given the amount of alpha synuclein expressed in red cells, so we ask question whether the alpha synuclein from red cells can be transmitted to the gut. So the second part of the study is to demonstrate the alpha synuclein contained in the extracellular vesicle, sometimes people call exosomes can carry alpha synuclein to the gut readily, whereas the free form alpha synuclein cannot.

And then we also discover that what's coming from the red cell alpha synuclein were mainly stopped at epithelial cells.

However, the epithelial alpha synuclein can be transmitted to the neurons locally. So that's our [00:06:00] hypothesis that the red cell containing alpha synuclein can come to the gut and eventually transmit to the brain via vagal nerve. That pathway has been demonstrated by many, many investigators.

[00:06:14] Dr. Tiago Outeiro: Yeah, that's that's true. And so we know this is like the highway through which synuclein can go into the brain. And so you talked about extracellular vesicles and exosomes. So do you have an estimate of what percentage of synuclein exists in the extracellular vesicles as compared to the free form?

Is it possible to estimate this?

[00:06:35] Dr. Jing Zhang: Right, so what we do know is that the in the blood the percentage of alpha synuclein existing in the plasma versus the different type of cells. We know about 98 to 99% of blood alpha synuclein is in the red cells. But what's the percentage of alpha synuclein contain in the extracellular [00:07:00] vesicles of the red cell secreted forms?

That part is yet to be decided. Oh, by the way, exosome is a well known phenomenon at this point, but to the very first paper talking about exosome is actually the description of the maturation of red blood cells where they will secrete exosomes like things they do not want into the extracellular vesicles.

Back then it's called the exosomes. So it's a long story between exosome, the secretion, and red cell morphology and physiology.

[00:07:34] Dr. Tiago Outeiro: That's really, really interesting.

And so now as you know, there are several studies showing that serum alpha synuclein can differentiate between Parkinson's and controls. So do you think this is brain derived or could this be erythrocytes derived alpha synuclein in the blood that goes into the serum?

[00:07:56] Dr. Jing Zhang: This is another excellent question. So because the [00:08:00] concentration of alpha synuclein in blood is higher, much higher than what's in the CSF. So it's more than likely alpha synuclein detected in the serum or plasma are coming from red cells. They're not from the central nervous system.

Even if it is a small minor component of alpha synuclein detected in the serum or plasma.

[00:08:24] Dr. Tiago Outeiro: Yeah, so this is really paradigm changing idea because everyone is very biased towards thinking that we are measuring synuclein coming from the brain, but in fact the majority of synuclein is in the blood, in the red blood cells. So it's highly likely that what we're measuring is blood synuclein.

And so this, this needs to be fully cleared and demonstrated. So as a pathologist do you think we can use blood synuclein as a biomarker? I'm guessing your answer, but I'd like to, to hear you on this.

[00:08:56] Dr. Jing Zhang: Clearly, I do believe the blood, especially the red [00:09:00] cell alpha synuclein can be a very important biomarkers for Parkinson's disease. The reason for that is we published a paper back in 2019 to demonstrate that the Parkinson's patients red cells are abnormal and also with increased oligomeric alpha synuclein in a membrane component of red cells.

So in that regard we also measured the alpha synuclein secreted by red cells and captured specifically by one type of exosomes. And then those exosome containing alpha synuclein in Parkinson's disease are different from those of controls. So taking all together we believe red blood cell containing alpha synuclein whether it's secreted by exosome or not. Can be very important biomarkers for Parkinson's and related Parkinson disorders.

[00:09:52] Dr. Tiago Outeiro: Great. So I think we've covered most of the discussion.

 Thank you so much for your time to discuss your paper. I think this is a very [00:10:00] exciting topic that I'm sure will interest many of our listeners. And so I really appreciate your time. 

[00:10:06] Dr. Jing Zhang: Thank you for inviting me for this interview. It's a pleasure .

[00:10:08] Dr. Tiago Outeiro: We've just interviewed Dr. Jing Zhang on his article on erythrocytic alpha synuclein and the gut microbiome, kindling of the gut brain axis in Parkinson's disease.

So thank you all for listening and join us in our upcoming podcasts. [00:11:00] 

Special thank you to:

Dr. Jing Zhang
Department of Pathology,
Zhejiang University School of Medicine

Tiago Outeiro, PhD 

Director of the Department of Experimental Neurodegeneration 

University Medical Center Goettingen, Germany

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