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[00:00:50] Dr. Outeiro:
We were very excited about your paper and I think we should start from the very beginning. So what are α-Synucleinopathies?
[00:00:58] Dr. Linard:
α-Synucleinopathies are a group of neurodegenerative diseases that includes two relatively frequent pathologies, Parkinson's disease and dementia with Lewy bodies, as well as a rarer condition, multiple system atrophy.
And these pathologies are characterized by different combination of motor, cognitive, or autonomic dysfunctions, but they do have at least one thing in common: They are all associated with an intracellular accumulation of the alpha-synuclein protein in the nervous system. Either, mainly neurons for PD and DLB of MSA in oligodendrocytes, which are the myelinating cells of the central nervous system. But in all these pathologies, the triggers of the accumulation of alpha-synuclein remains to be clarified.
So do we really have reasons to think Parkinson's disease and other synucleinopathies may be triggered by infectious agents? Can you summarize the main ideas of your review article?
Personally, I think that we have at least enough reason to investigate it.
So in our review, we attempted to see how the involvement of infectious agent could explain the type of deposits found in synucleinopathies. Their topography, the temporal sequence of the disease, and the profile of patients in terms of genetic or environmental risk factors. Therefore, we discussed studies highlighting that several infectious agents can trigger the accumulation of the alpha-synuclein protein, and the study suggesting the potential role of alpha-synuclein in the anti-microbial defense.
Then we discussed the hypothesis is that early symptoms of synucleinopathies may reflect the entry point of infectious agents. Indeed, hyposmia and gastrointestinal issues in PD and DLB or neurogenic urinary symptoms and erectile dysfunction in some patient with MSA could reflect a triggering effect of infectious agents in contact with nerve endings in several mucous membranes.
We also briefly discussed how potential changes in the immune response with age may explain the relatively late age of onset of synucleinopathies, and sought to identify elements suggesting that some of the risk factors of synucleinopathies could modulate the impact of infections on the nervous system, in particular as links appear to exist between some genetic risks factor infection.
And finally, we discussed previous studies or reviews assessing the association between specific infectious agents and the onset of synucleinopathies in humans.
[00:03:58] Dr. Outeiro:
You come to the question of whether alpha-synuclein may be an anti-microbial peptide. So why would we think this?
I think that this hypothesis could be based on five elements: structural similarities with known anti-microbial peptides, a sequence which is highly conserved among vertebrates and may reflect some biological importance, it's induction by several infectious agent, and finally its potential anti-microbial role and immunomodulatory role.
To detail some of this bunch a little more, we can know that alpha-synuclein aggregation can be induced in neurons of inside the central enteric nervous system following innoculation with different infectious agents in both virtual models and in rodents. And in humans, an increased expression of alpha-synuclein was also detected in brain samples or in enteric neurons following infections by several viruses.
And finally the potential anti-microbial role of alpha-synuclein is based on one in-vitro study highlighting its anti-microbial properties against several bacteria and fungi. And on two studies showing that SNCA knockout mice reported more severe outcomes compared to their wild type litter mates after inoculation of these pathogens. And these outcomes included higher intracerebra l viral load and higher mortality rates due to infection.
So all in all, this hypothesis seems to me very interesting. But obviously, it still needs to be consolidated.
This is interesting, but it just makes me confused because, is α-synuclein not a protein involved in synaptic vesicle trafficking and homeostasis? In the end, how many functions does alpha-synuclein have?
[00:05:59] Dr. Linard:
Indeed, some studies have suggested that alpha-synuclein is involved in synaptic plasticity and neurotransmitter or vesicle transport. In particular, the studies highlight that alpha-synuclein predominantly binds to vesicle-forming membranes in the presynaptic nerve terminal.
Nevertheless, these hypothesis remain discussed, as it does not explain the role of alpha-synuclein in other cell compartments, such as nucleus or mitochondria. Or in other types of cells, such as red blood cells for example However, a role in vesicle trafficking is perhaps not completely incompatible with a role in antimicrobial defense.
Indeed the Britain colleague suggested that alpha-synuclein may bind small vesicles, such as those carrying endocytosed viruses.
Okay. I see. That makes sense. So are synucleinopathies special in comparison to other neurodegenerative disorders? Or could there also be a connection between infection, infectious agents and Alzheimer's disease, Huntington's disease and other neurogenerative disorders?
Nope, synucleinopathies are not special regarding a potential connection with infectious agents. I don't know the literature on intent and disease, but what is called the infectious hypothesis, or anti-microbial hypothesis, is widely investigated in AD as well as in amyotrophic lateral sclerosis, for example.
And in my opinion, this is what is particularly interesting. To consider a pathophysiological mechanism, which could be at least partially common between these neurodegenerative diseases that have a lot in common. Notably, studies assessing a potential anti-microbial role of the amyloid peptide implicating AD are far more numerous than the studies on alpha-synuclein.
And some studies are starting to appear on peptide implicating other neurodegenerative diseases, such as TAU, TDP-43 or FUS.
[00:08:10] Dr. Outeiro:
When we talk about this interplay between alpha-synuclein and infectious agents, what agents are we really talking about? Are we talking about bacteria, viruses, parasites? Are we talking, for example, about viruses like SARS-COV-2, the COVID-19 virus?
[00:08:26] Dr. Linard:
In my opinion, regarding synucleinopathies, no type of infectious agent is to be ruled out at this stage of the reflection. We should even complete your list with fungi. So as you can see, a lot remains to be done, even though I admitted personal appetite for neurotropic viruses, because of that ease in spreading from neurons to neurons.
Regarding the existing literature on Parkinson's disease, we're discussing now review the pre-existing reviews on the infectious hypothesis, which have become quite numerous lately. And it should be of particular interest on the impact of gut microbiota, and more particularly on its bacterial path, probably due to the suspect involvement of the gut-brain axis and the available techniques allowing a relatively easy study of bacteria.
And regarding the DLB and MSA, our systematic literature review highlgihts 23 articles published before June, 2021. All these studies were relatively small and the infectious agents studied were quite varied. Again, with a certain focus on gut micro biota, but this time in MSA. Overall, there does not seem to be any sufficiently solid evidence to suspect the involvement of a particular infectious agent in these pathologies for the moment.
More specifically on COVID, I do not know in detail the latest pieces of literature on this rapidly evolving subject, but to my knowledge, several in-vitro studies have shown that SARS-COV-2, upregulates the expression and aggregation α-synuclein. A study on non-human primates have also highlighted the formation of Lewy bodies in the brains after virus innoculation. And in humans a bad form of symptoms, suggest see post-meal and us now, which have been widely publicized. Cases of infected patients developing Parkinsonian symptoms have also been described. Nevertheless, in my opinion, this is not enough to predict an impact of the virus and the risk of developing slowly, progressive neurodegenerative diseases such as α-synucleinopathies. I think it would require either a relatively long-term persistence of the virus in the body, which is not the case, I believe for SARS-COV-2, or an ability of the virus to trigger a chronic and deleterious inflammatory phenomenon after an acute infection. But in any case, it is clearly something that we will have to assess in the years to come.
[00:11:16] Dr. Outeiro:
Yeah. That's, that's very true. I agree. And so also, if you think about this interplay with infectious agents, would you think that antibiotics, antiviral agents, anti-fungic agents may have any potential as therapeutic tools in synucleinopathies?
So for example, my group was involved in some work together with some colleagues from Brazil, from France and Argentina, on the effects of doxycycline, which is an antibiotic, as a molecule that may have some beneficial properties against alpha-synuclein aggregation. Do you think it's worth looking further into the actual effects of antibiotics, for example, of these other anti -infectious agents, molecules in Parkinson's disease and in synucleinopathies in general?
[00:12:03] Dr. Linard:
Yes. If in the future, we identify more clearly the impact of specific infectious agents on synucleinopathies, anti-infective treatments will certainly have a role to play either therapeutically or preventively. But in my opinion, we haven't reached that stage yet for synucleinopathies.
And regarding the studies carried out on doxycycline, this goes a little outside the scope of the infectious hypothesis. As you said, doxycycline is not studied there for its antibiotic properties, but rather in relation to anti-inflammatory properties or to an ability to reduce the aggregation of anomeric proteins such as α-synuclein. So, yes, in my opinion, it seems an interesting molecule to study, but not within the framework of the infectious hypothesis, for the moment, at least.
[00:13:00] Dr. Outeiro:
Thank you so much for your time, Morgan. It has been a pleasure having you on the MDS Podcast.
We have just interviewed Dr. Morgan Linard, and we discussed the article "Infectious Agents as Potential Drivers of α-Synucleinopathies" published recently in the Movement Disorders journal. So don't forget to download the article for more details.
Thank you all for listening, and join us in our upcoming podcasts.
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