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We are going to discuss his recent paper, published it in the Movement Disorders Journal, mitochondrial DNA, copy number as a potential biomarker for the severity of motor symptoms and prognosis in Parkinson's Disease. Welcome to the MDS Podcast professor.
[00:00:52] Prof. Sun Ju Chung: Thank you so much for inviting me and thank you so much for this opportunity.
[00:00:57] Dr. Sarah Camargos: Of course. Let's start with the [00:01:00] basics. Why study mitochondrial DNA copy number in Parkinson's disease and how does it reflect mitochondrial health?
[00:01:09] Prof. Sun Ju Chung: Parkinson's disease is a heterogeneous and common complex disease. We don't know the exact etiology yet, but the genetic factor is very important for the development of Parkinson's disease. Over the last two decades, we focused on the nuclear DNA variation, and we found that more than 10, mutations related to the familiar Parkinson's disease with high effect size.
And we also found more than 90 genetic variations related to the sporadic Parkinson's disease. But there are still Missing heritability in the genetics of Parkinson's disease. So we expanded our scope of genetics we investigated other aspect of [00:02:00] DNA which is the mitochondrial DNA.
As we know, mitochondrial dysfunction is very important, pathophysiology in the development of Parkinson's disease. And we are specifically interested in the mitochondrial DNA copy number because mitochondrial DNA copy number refers to the number of copies of mitochondrial DNA present in a cell.
And we think that the mitochondrial copy number is an easily accessible proxy for mitochondrial function. So we investigate the mitochondrial copy number using a peripheral blood as a biomarker for Parkinson's disease.
[00:02:41] Dr. Sarah Camargos: What approach did you choose to assess this mitochondrial DNA copy number and why did you choose such method?
[00:02:50] Prof. Sun Ju Chung: But there are several method to assess the. Mitochondrial copy number and we choose the whole genome sequencing [00:03:00] method. Previous study used the quantitative PCR, but it has some limitation because it is selected certain number of genes or certain number of genomic area to be investigated.
But whole genome sequencing covers all genomic area. It has very comprehensive research to investigate our genome. And we calculated mitochondrial copy number based on the observed ratio of sequence coverage between mitochondrial DNA and original DNA, because each cell contains two copies of original DNA. We extracted reads from the autosomal regions to calculate mean nuclear DNA coverage. And then we mapped read on the mitochondrial genome and estimated the coverage. We called it as mean mitochondrial DNA coverage. We calculated the mitochondrial count number level using the calculation as [00:04:00] two by mitochondrial coverage divided by nuclear DNA coverage.
And we thought that we represent mitochondrial DNA copy number in whole genome in a single patient.
[00:04:13] Dr. Sarah Camargos: Yes, thorough. How was your cohort selected?
[00:04:19] Prof. Sun Ju Chung: Yes we selected a PD patient from our outpatient clinic and we selected the health control collected also from our outpatient clinic. And we used the 405 patients in Our, outpatient movement disorder clinic. And also we collected samples from the health controls who gave us a consent to involved in this study.
[00:04:47] Dr. Sarah Camargos: Yes, I thought you were very thoughtful because you select the patients that didn't have mutations on several genes [00:05:00] linked to mitochondrial DNA too. This fantastic. What were the key outcomes of your study?
[00:05:08] Prof. Sun Ju Chung: The main results we found was mitochondrial DNA copy number levels. Were significantly lower in patient with Parkinson's disease compared with healthy controls. And we found that there was a negative correlation between the mitochondrial copy number level and motor severity in Parkinson's disease patients. And more importantly, we found that there was an association between lower mitochondrial copy number levels. And higher risk of developing dementia in patients with Parkinson's disease. However, we did not find any significant correlation between mitochondrial DNA copy number level and the brain motor complication in Parkinson's disease.
[00:05:56] Dr. Sarah Camargos: Such as levodopa induced dyskinesia, right?
[00:05:59] Prof. Sun Ju Chung: [00:06:00] You're correct.
[00:06:01] Dr. Sarah Camargos: Very interesting. And what do you think that are the limitations of your study?
[00:06:08] Prof. Sun Ju Chung: We used 410 patients with Parkinson's disease and uh, 200 healthy control. So, That study sample number is relatively small and which has inherent limitation because of the small sample size. Secondly, we included patient with variable disease durations as study enrollment, but we addressed this limitation by analyzing a subgroup of early stage Parkinson's disease patients.
And finally, we measured mitochondrial DNA copy number levels at a single time point to potentially missing changes. Mitochondrial copy number levels over time. So serial assessment, mitochondrial copy number levels is leading in the future study.
[00:06:58] Dr. Sarah Camargos: Yes, [00:07:00] and given the varying levels of heteroplasmy across tissues, particularly in the brain and blood, is blood derived mitochondrial DNA a reliable source for your conclusions?
[00:07:14] Prof. Sun Ju Chung: I think it's a very important question. But unfortunately there is a little study to investigate the correlation between the blood mitochondrial copy number level and other tissue including brain and, but some study demonstrate the nice correlation between the blood mitochondrial DNA copy number label and tissue mitochondrial RNA expression in non blood tissues.
So, I think it's it's a very important issue and we need to investigate further about mechanistic link between the blood mitochondrial copy number and brain mitochondrial function or mitochondrial copy number in the brain tissue in patient with [00:08:00] Parkinson's disease.
[00:08:01] Dr. Sarah Camargos: Yes, definitely, it should be very interesting to see if there is a strong correlation. Were GBA or APOE statuses investigated in your PD population?
[00:08:15] Prof. Sun Ju Chung: I think it's a very important question because the two genes are very closely related to the dementia in Parkinson's disease and other neurodegenerative disorders. As I said unfortunately we have very small sample size, and when we stratified study samples according to the GBA status and APOE status the statistical power was not enough to calculate the true effect of the mitochondrial copy number in the development of Parkinson's disease and other symptomatology when I think it it should be done in the future study and I expect that there is some interesting findings when we stratified our study samples according to the GPA and APOE
and our future [00:09:00] study may include in inaction between the GBA and mitochondrial copy number or APOE status and mitochondrial copy number levels. I think it's a very important issue.
[00:09:12] Dr. Sarah Camargos: Yeah. Maybe something related and something mechanistic between these genes and mitochondrial DNA. Yes. So do you foresee further studies like yours, emphasizing mitochondrial DNA copy number as a potential biomarker in Parkinson's disease?
[00:09:33] Prof. Sun Ju Chung: Yes, we hope that mitochondrial copy number reversed. Maybe the potential biomarker in the diagnostics and prognostics in Parkinson's disease. So we hope that we continue to investigate the mitochondrial DNA copy number in the future study and validate our findings and we hope that we develop the useful [00:10:00] biomarker for Parkinson's disease using mitochondrial DNA copy number.
[00:10:04] Dr. Sarah Camargos: Yes and what is the clinical applicability of having a biomarker for Parkinson's disease, Dr. Chung?
[00:10:13] Prof. Sun Ju Chung: That will be our final goal because we are developing many kinds of biomarkers for Parkinson's disease. Uh, I think the the blood biomarker is a very important force because it's very accessible and very easy to obtain from our patient and our patient have no negative feeling about blood sampling compared to other CSF studies or other studies.
This study used blood samples and if we develop the blood biomarkers using a mitochondrial copy number it can contribute to the diagnostics in Parkinson's disease. Because although we developed this several biomarkers, we still have certain level of misdiagnose weight for the diagnosis of [00:11:00] Parkinson's disease and furthermore in terms of prognostics for example development of dementia, development of limb, or complication development of motor symptoms.
Can develop this blood, biomarkers using mitochondrial DNA and this will be the, very nice very useful biomarker for the prognostics of Parkinson's disease in the future, I hope.
[00:11:24] Dr. Sarah Camargos: We hope. And what are your next steps in this field?
[00:11:28] Prof. Sun Ju Chung: We are continue to study Of mitochondrial DNA and nuclear DNA. Next step will be to investigate changing interaction between mitochondrial DNA copy number or mitochondrial genes with nuclear DNA. As I said we know the very important cordial mutation for Parkinson's disease, and we know that m ore than 90 genetic variation relative to the sporadic Parkinson's disease. But there has been little study about [00:12:00] the interaction between a nuclear gene and mitochondrial genes, so we hope we can study the gene interaction between nuclear and mitochondrial genes.
And as I said yeah, we are conducting, next step genetic studies to develop these genetic findings as new blood biomarkers. We hope to use more large size of a sample to validate our findings And hope to develop a new blood biomarker for Parkinson's disease patient in the future.
[00:12:30] Dr. Sarah Camargos: And this is, it's amazing, it's completely interesting field and it's easy to take a blood for our patients, although it's a little bit expensive nowadays. But hopefully things are going to be easier don't you think?
[00:12:46] Prof. Sun Ju Chung: Absolutely. You're right. I agree. Yeah.
[00:12:50] Dr. Sarah Camargos: Thank you, Professor Chung, for your time with us and have a nice day.
[00:12:55] Prof. Sun Ju Chung: Thank you so much.