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Does glucocerebrosidase activity correlate with disease risk or phenotype severity in Parkinson's disease?

April 11, 2022
A discussion with Dr. Avner Thaler on the findings and implications of a study on the background of importance of GBA mutations and GCase activity in Parkinson's disease. Read the Article.

[00:00:00] Dr. de Pablo-Fernández:
Hello, everyone. And welcome to a new episode of the MDS Podcast, the official podcast channel of the International Parkinson and Movement Disorders Society. My name is Eduardo de Pablo-Fernández from the University College London Queen Square Institute of Neurology, and I have the pleasure of welcoming today Dr. Thaler to discuss his paper. "Glucocerebrosidase Activity is not Associated with Parkinson's Disease Risk or Severity."

Welcome to the MDS podcast, Dr. Thaler, and thank you for your time.

View full transcript

[00:00:38] Dr. Thaler:
Thank you very much.

[00:00:40] Dr. de Pablo-Fernández:
Dr. Avner Thaler is a neurologist at the Neurological Institute, Tel Aviv Medical Center, and he has ample expertise and research experience evaluating GBA and LRRK2 mutations.

So before we discuss your paper, I would be grateful if I could use your expertise on this topic to discuss a bit the importance of GBA mutations, which is considered the most significant genetic risk factor for Parkinson's disease. And if you can tell us a bit more on the influence of these mutations in the phenotype of people with Parkinson's disease.

[00:01:17] Dr. Thaler:
Okay. So the GBA gene encodes a lysosomial enzyme called beta-glucocerebrosidase. Homozygous carriers of mutation in the gene suffer from a disease that is called Gaucher's disease. And through those patients, clinical observations found that their first-degree relatives had relatively high rates of Parkinson's disease.

About 20 years ago, several publications surfaced with the link and then a more formalized paper in the New England Journal of Medicine actually found the connection between heterozygous GBA mutation, carriers, and risks for PD. The mutations in the GBA genes can be split into severe mutations, which are associated with Gaucher disease; mild mutations, which are associated with less severe forms of Gaucher disease; and variant mutations, which are associated with Parkinson's disease, but not with Gucher's disease.

There are more than 300 recognized mutations in the gene today. And it has been relatively thoroughly researched in the past 10 years with both genotype, phenotype correlations and disease phenotype associations. And what came out is that relative to idiopathic Parkinson's disease, or Parkinson's disease that is not caused by a known genetic mutation, mutations in the GBA genes cause a more severe form of Parkinson's disease, especially those with the more severe mutations. Both in the motor aspect of the disease and in the non-motor aspects of the disease, more severe cognitive decline, more non-motor symptoms, higher rates of hallucinations, and also earlier age of onset of the disease.

[00:03:20] Dr. de Pablo-Fernández:
That's very interesting. As you mentioned, the GBA gene encodes the protein glucocerebrosidase, GCase for abbreviation. And one of the interesting topics of evaluating people with genetic mutations is trying to understand the pathogenic mechanisms underlying Parkinson's disease.

And this GCase activity has been associated with the accumulation of synuclein, not just in people with these mutations, but also in people with sporadic Parkinson's disease. What are your thoughts on that?

[00:03:56] Dr. Thaler:
The exact mechanism of how a GCase deficiency is associated with Parkinson's disease risk is not clear yet. There are several theories that are currently circulated and they're not necessarily contradictory. They can be separated grossly into two: one is that the mutation causes a loss of function with substrate accumulation. And that has been shown to be associated with alpha-synuclein aggregation and even some kind of a positive loop between lower GCase activity and alpha-synuclein aggregation and so forth.

There is another theory that actually thinks that there's a gain of function due to the mutation with ER stress and eventual cell death. Again, it's not yet determined which one actually is right, or whether there's a combination of the two. But, as you said, even in idiopathic PD, in patients that do not have mutations in the GBA gene, some studies have detected lower GCase activity, either in cells or in biopsies. So there must be some kind of a role of GCase even in non-GBA carriers. But that definitely needs further investigations.

[00:05:17] Dr. de Pablo-Fernández:
As you said before, these theories may be complimentary, because with Parkinson's disease is very heterogeneous from a clinical point of view and also from a pathogenic point of view. Focusing now on your paper: So your study assessed participants of the BEAT-PD study — a specific population, which is very interesting as they present a higher rate of mutations. And it's a population at risk of developing Parkinson's disease. Can you tell us a bit more about the participants of your study?

[00:05:47] Dr. Thaler:
Yes, among Ashkenazi Jews, mutations in both the GBA gene and the G2019S mutation and the LRRK2 genes are very common. Up to a third of our Ashkenazi Jewish PD cohort are positive to at least one of those mutations. Almost, I think the highest rate worldwide. So we have a very interesting cohort. We've ascertained genetic status of more than 3000 PD patients throughout the years.

And about six or seven years ago, we teamed up with Biogen for a natural history study, which collected 800 participants: 300 PD patients and 500 first- degree relatives. The idea was to collect idiopathic PD, meaning PD patients that do not harbor mutations in either the LARC two or the GBA, and compare them to patients with mutations in the GBA gene and in the LRRK2 gene. And to collect healthy controls without mutations and healthy, non-manifesting carriers of mutations in the GBA and the LRRK2 gene. Some of them were followed up longitudinally every year and most of them were just cross-sectionally assessed. That cohort is actually the basis of the paper that we are currently discussing. The specific study was also funded by the Michael J. Fox Foundation and Silverstein foundation for Parkinson's with GBA.

[00:07:12] Dr. de Pablo-Fernández:
Thank you, that's very interesting. I find that that non manifesting carrier population that are at risk of developing Parkinson's disease is particularly interesting. And the results of your study show that GBA mutations in general correlate well with GCase activity, but they don't show much correlation with regards to phenotype of Parkinson's disease, motor, and cognitive.

And with non-manifesting carriers, they don't associate with prodromal symptoms. Basically, they don't show a higher risk of prodromal Parkinson's disease based on the MDS diagnostic criteria. There are conflicting results in the literature about these associations.

How would you explain the results that you found in your study and how would you compare your results with other previous studies that have assessed GCase activity and phenotype in Parkinson's disease?

[00:08:12] Dr. Thaler:
Well, I think he described the results of very accurately. We found lower GCase activity among the different PD participants with the different mutations — the mild mutations, the severe mutations and the variant mutations. Among non-manifesting carriers of the GBA mutations, we found reduced GCase activity as well.

There was no significant difference within the groups or between the groups. There wasn't anything that separated a PD GBA carrier from a non-manifesting PD carrier. And the variance of the GCase activity was pretty wide.

I have to emphasize that we used dry blood spots for the assessment of the GCase activity, which is what most publications to date have used. So the method itself is pretty valid. It's what has been used up to now. There could be different methods ascertain ing GCase activity in PBMC, in CSF, but most of the literature to date have used the same method as we did.

We did try to see whether the severity of the mutation influenced the results. We did a sub-analysis of just the most common mild GBA mutation among Ashkenazi Jews, which is the N370S mutation. And we found that the results did not change. We have found the same results. I have to mention that the the proportions of mild mutations in the cohort reflected their proportion in the Ashkenazi Jewish population.

 There are a lot of mild mutation carriers relative to severe mutation. We were relatively low and severe mutation carriers. That might influence the results as well, even though previous publication had relatively similar proportions of mild and severe. This is one of the largest cohorts to be assessed for the GCase activity.

So previous studies that did find a signal might have been underpowered. But we do feel pretty confident that GCase activity per se is not what is responsible for the GBA association with PD. There should be other factors that come into play — other genetic factors, other environmental factors, age, what have you — that should be involved. And it is not a simple level of enzyme that could explain the risk and severity of the disease.

[00:10:45] Dr. de Pablo-Fernández:
Finding a reliable biomarker for PD has been challenging so far and so, I don't know if you feel pretty confident that GCase is unfortunately not going to provide that reliable information, that would be really useful for clinical decisions and prediction of carrying the future.

 We have this cause that Parkinson's disease is a very heterogeneous from a clinical point of view, and I don't know what your thoughts would be in them providing more not just cross-sectional, but longitudinal assessment of GCase activity. I don't know if that would add any value to the possibility of GCase activity as a biomarker, or you think that the variation over time wouldn't be important from a disease marker point of view?

[00:11:36] Dr. Thaler:
It's definitely something that needs to be assessed. There haven't been a lot of studies that assess the longitudinal influence of time over the phenotype and the levels of GCase activity. I would be surprised if they would be positive, but it's definitely something that needs to be done.

I think the field needs to open up to the whole cascade, and not just the GCase activity. Perhaps upstream or downstream enzymes are relevant as well. That is being done.

I'm not sure how much CSF will have an influence. There's been little publications regarding the stability of GCase in CSF.

And I think perhaps an association between activity and synuclein aggregation on synuclein assay aggregate might have some more information that is still missing on RT-QuICs, for instance. That is something that is needed as well.

So there is a lot of work to be done. And hopefully we'll be able to answer it in due time.

[00:12:42] Dr. de Pablo-Fernández:
Indeed there is. One interesting point that you mentioned is again, going back to the potential involvement of GCase activity in alpha-synuclein aggregation and therefore PD pathogenesis ... there is ongoing trials that are targeting GCase activity with products like ambroxol, for example, with the potential of using this target as disease modifying therapies.

So we are moving from GCase activity as a biomarker of disease progression or risk of Parkinson's disease. But now due to the potential pathogenic involvement, we are moving to a potential target for therapies. As you said, there is some evidence supporting this, but there's still a lot of unanswered questions.

I don't know what your thoughts are about the potential use of GCase activity as a therapeutic target.

[00:13:35] Dr. Thaler:
There are several companies that are in the market currently. I think that last year we had the interim results of new fees trial, which was closed earlier than expected with no positive results, or it was a disappointment. The ambroxol and the other studies, the LTI is opening a study in GBA. I think it's a valid target. I'm pretty convinced the GCase itself is not the target, but the GBA gene might be able to teach us, hopefully for the GBA PDs and hopefully even more for the idiopathic PDs, I am still hopeful. And I hope that we'll get positive results.

The ambroxol phase II showed positive results up to now.

[00:14:18] Dr. de Pablo-Fernández:
That's very interesting. My impression is that I say it is clinically. I think Parkinson's disease is likely to be very heterogeneous from a pathogenic point of view. And I think probably we need to have better biomarkers and more tests to identify which pathogenic mechanisms are relevant for what group of patients. And probably that will lead to the development of more targeted therapies for specific populations. And I think probably GBA mutations and GCase activity may be one of these areas that are going to be very useful, but only for a certain population of Parkinson's disease.

[00:14:56] Dr. Thaler:
Right. Yeah, same goes for LRRK2 mutations. There are several companies that are looking into ASO's and other mechanisms of intervening the cascade in the LRRK2 mutation. And I think general alpha-synuclein therapies might be relevant definitely for the GBA PD, because I think it's almost a hundred percent certain that GBA PD will have alpha-synuclein as opposed to the LRRK2 PDs, which we know have a more heterogeneous pathology and less than 50% of them harbor alpha-synuclein when tested. So there are interesting options for moving forward for tailored treatments. And I think it's a, it's an interesting time to study Parkinson's.

[00:15:40] Dr. de Pablo-Fernández:
Certainly it is a very interesting era. And hopefully, as you said, things will continue to move forward. I would like to thank you for your time and expertise and sharing your knowledge with me and the MDS podcast listeners. I hope you enjoyed the experience and I hope to have you here soon with another interesting study.

[00:16:02] Dr. Thaler:
Thank you very much for the opportunity.


Special thank you to:

Dr. Avner Thaler MD, PhD

Eduardo de Pablo-Fernández, MD, PhD 

Department of Movement and Clinical Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom

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