Researchers from Düsseldorf (Germany) and a biotech company in San Francisco have published a research report in which they present evidence that the H1N1 influenza A virus can cause the Parkinson’s-associated protein alpha synuclein to start aggregating in neurons (both in cell culture and mice).
In addition, they reported that an influenza drug blocked this aggregation effect.
In today’s post, we will discuss what H1N1 influenza virus is, what the new research report found, and we will consider what this means for Parkinson’s.
The date today is the 11th March, 2020.
Based on the news headlines trending on all forms of media, it is probably the absolute worse moment to consider writing a post about how a particular viral infection could be playing a role in Parkinson’s,… but here we are.
Over night a research report was published that immediately grabbed my attention.
This is the report:
Title: Disruption of cellular proteostasis by H1N1 influenza A virus causes α-synuclein aggregation.
Authors: Marreiros R, Müller-Schiffmann A, Trossbach SV, Prikulis I, Hänsch S, Weidtkamp-Peters S, Moreira AR, Sahu S, Soloviev I, Selvarajah S, Lingappa VR, Korth C.
Journal: Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201906466. [Epub ahead of print]
In this study, the researchers reported that infection by the H1N1 influenza A virus (very different to the current coronavirus COVID-19) can cause accumulation and aggregation of the Parkinson’s-associated protein alpha synuclein.
Remind me, what is H1N1 influenza?
Canadian scientists recently reported that mice with a specific genetic variation – in the Parkinson’s-associated LRRK2 gene – differ in how they are able to deal with bacterial and viral infections.
Curiously, mice with the Parkinson’s-associated LRRK2 mutation could handle a bacterial infection better than normal mice, while mice with no LRRK2 protein struggled against the infection. And the researchers found that this effect was most prominent in female mice in particular.
And curiously, when the mice are infected with a dangerous virus, female mice with the Parkinson’s-associated LRRK2 mutation fared worse than their male counterparts.
In today’s post, we will discuss what LRRK2 is, review the new research, and explore what the sex difference could mean in terms of Parkinson’s.
Autumn colours. Source: Visitsunlimited
I am a big fan of Autumn.
The colours and the crisp/bracing air. I love the long, slow afternoon strolls and anticipation of the festive season to come.
But most of all I love the license to eat all the good wintery food. After a summer of salads and light food, there is nothing better that entering a warm cottage or pub, and smelling the hearty food (my wife if French – we navigate based on the quality of eateries).
Autumn bliss. Source: Askdrake
But there is a down side to autumn: The start of the flu season.
Luckily, our immune systems are pretty robust – doing battle on a moment-to-moment basis with all manner of pathogenic agents.
Recently, some Canadian scientists discovered something interesing about the immune system and it relates to Parkinson’s.
What did they find?
New data from researchers in Taiwan has intriguing implications for our understanding of the development of Parkinson’s.
An analysis of the enormous national medical database pointed towards towards hepatitis C viral infections as a risk factor for developing Parkinson’s.
But here is the twist in the tale: Interferon-based antiviral therapy reduces that risk back to normal.
In today’s post, we will review the new research, discuss what interferons are, explore what other research has been conducted on interferons in the context of Parkinson’s, and consider the implications of this new research for Parkinson’s.
We have learnt a great deal about Parkinson’s over the last few years via the use of “big data”.
Whether it be the analysis of vast pools of genetic information collected from tens of thousands of individuals with the condition, to analysing massive datasets of longitudinal medical information, these investigations has open new avenues of research and investigation.
For example, “big data” studies have demonstrated that those who smoke cigarettes and drink coffee have a reduced chance of developing Parkinson’s (click here to read a previous SoPD post on this topic). ‘Big data studies have also pointed towards novel therapeutic approaches (click here for a previous SoPD post highighting an example).
Recently, an analysis of medical records from Taiwan have shed new light on another potential influencer of Parkinson’s risk: Hepatitis C
What is Hepatitis C?
Earlier this year, a San Francisco-based biotech company – called Cortexyme – published a research report that grabbed my attention.
The study presented data supporting an alternative theory of the cause of Alzheimer’s – one in which a bacteria involved in gum disease appears to be playing a leading role – and evidence that the company’s lead experimental compound COR388 could have beneficial effects in the treatment of the condition.
While the study was intriguing, what completely blew my mind was the fact that the company had already tested COR388 in a couple of Phase I clinical trials, and since then they have initiated a large Phase II/III trial.
In today’s post, we will discuss this new theory of Alzheimer’s, look at what Cortexyme are doing, and how this could relate to Parkinson’s.
The dashed lines show associations. Source: Slideplayer
Before we start today’s post, a word on ‘associations‘.
Please remember while reading this material that association does not equate to causation.
So if I write something like “researchers have found an association between a type of bacteria that causes gum disease and Alzheimer’s”, it does not mean that someone with either condition necessarily has the other. It only means that they have both simply appeared in the same individuals at a higher than chance rate.
So what is today’s post about?
A very interesting report in which researchers have found an association between a type of bacteria that causes gum disease and Alzheimer’s.
In addition to looking at current Parkinson’s disease research on this website, I like to look at where technological advances are taking us with regards to future therapies.
In July of this year, I wrote about a new class of engineered viruses that could potentially allow us to treat conditions like Parkinson’s disease using a non-invasive, gene therapy approach (Click here to read that post). At the time I considered this technology way off at some point in the distant future. Blue sky research. “Let’s wait and see” – sort of thing.
So imagine my surprise when an Italian research group last weekend published a new research report in which they used this futurist technology to correct a mouse model of Parkinson’s disease. Suddenly the distant future is feeling not so ‘distant’.
In today’s post we will review and discuss the results, and look at what happens next.
Technological progress – looking inside the brain. Source: Digitial Trends
I have said several times in the past that the pace of Parkinson’s disease research at the moment is overwhelming.
So much is happening so quickly that it is quite simply difficult to keep up. Not just here on the blog, but also with regards to the ever increasing number of research articles in the “need to read” pile on my desk. It’s mad. It’s crazy. Just as I manage to digest something new from one area of research, two or three other publications pop up in different areas.
But it is the shear speed with which things are moving now in the field of Parkinson’s research that is really mind boggling!
Take for example the case of Squalamine.
In February of this year, researchers published an article outlining how a drug derived from the spiny dogfish could completely suppress the toxic effect of the Parkinson’s associated protein Alpha Synuclein (Click here to read that post).
The humble dogfish. Source: Discovery
And then in May (JUST 3 MONTHS LATER!!!), a biotech company called Enterin Inc. announced that they had just enrolled their first patient in the RASMET study: a Phase 1/2a randomised, controlled, multi-center clinical study evaluating a synthetic version of squalamine (called MSI-1436) in people with Parkinson’s disease. The study will enrol 50 patients over a 9-to-12-month period (Click here for the press release).
Wow! That is fast.
Yeah, I thought so too, but then this last weekend a group in Italy published new research that completely changed my ideas on the meaning of the word ‘fast’. Regular readers will recall that in July I discussed amazing new technology that may one day allow us to inject a virus into a person’s arm and then that virus will make it’s way up to the brain and only infect the cells that we want to have a treatment delivered to. This represents non-invasive (as no surgery is required), gene therapy (correcting a medical condition with the delivery of DNA rather than medication). This new study used the same virus we discussed in July.
In this post I review recently published research describing interesting new gene therapy tools.
“Gene therapy” involved using genetics, rather than medication to treat conditions like Parkinson’s disease. By replacing faulty sections of DNA (or genes) or providing supportive genes, doctors hope to better treat certain diseases.
While we have ample knowledge regarding how to correct or insert genes effectively, the problem has always been delivery: getting the new DNA into the right types of cells while avoiding all of the other cells.
Now, researchers at the California Institute of Technology may be on the verge of solving this issue with specially engineered viruses.
Gene therapy. Source: yourgenome
When you get sick, the usual solution is to visit your doctor. They will prescribe a medication for you to take, and then all things going well (fingers crossed/knock on wood) you will start to feel better. It is a rather simple and straight forward process, and it has largely worked well for most of us for quite some time.
As the overall population has started to live longer, however, we have become more and more exposed to chronic conditions which require long-term treatment regimes. The “long-term” aspect of this means that some people are regularly taking medication as part of their daily lives. In many cases, these medications are taken multiple times per day.
An example of this is Levodopa (also known as Sinemet or Madopar) which is the most common treatment for the chronic condition of Parkinson’s disease. When you swallow your Levodopa pill, it is broken down in the gut, absorbed through the wall of the intestines, transported to the brain via our blood system, where it is converted into the chemical dopamine – the chemical that is lost in Parkinson’s disease. This conversion of Levodopa increases the levels of dopamine in your brain, which helps to alleviate the motor issues associated with Parkinson’s disease.
Levodopa. Source: Drugs
This pill form of treating a disease is only a temporary solution though. People with Parkinson’s disease – like other chronic conditions – need to take multiple tablets of Levodopa every day to keep their motor features under control. And long term this approach can result in other complications, such as Levodopa-induced dyskinesias in the case of Parkinson’s.
Yeah, but is there a better approach?
Some researchers believe there is. But we are not quite there yet with the application of that approach. Let me explain:
Our apologies to anyone who is squeamish about needles, but this is generally how most people get their seasonal flu vaccination.
Why are we talking about flu vaccines?
Because new research, published last week, suggests everyone should be going out and getting them in the hope of reducing our risk of Parkinson’s disease.
In today’s post we will review the research, exactly what a flu vaccine is, and how it relates to Parkinson’s disease.
Electron micro photograph of Influenza viruses. Source: Neuro-hemin
Long time readers of the SoPD blog will know that I have a particular fascination with theories regarding a viral or microbial role in the development of Parkinson’s disease (the ‘idiopathic’ – or arising spontaneously – variety at least).
Numerous reasons. For example:
- The targeted nature of the condition (why are only selective groups of cells are lost in the brain during the early stages of the condition?)
- The unexplained protein aggregation (eg. Lewy bodies; could they be a cellular defensive mechanism against viruses/microbes – Click here to read more on this idea)
- The asymmetry of the onset (why do tremors start on only one side of the body in most cases?)
And we have previously discussed research here on the website regarding possible associations between Parkinson’s disease and and various types of viruses (including Hepatitis C, Herpes Simplex, and Influenza).
Today we re-visit influenza as new research has been published on this topic.
What is influenza?
Influenza is a single-stranded, RNA virus of the orthomyxovirus family of viruses.
A schematic of the influenza virus. Source: CDC
It is the virus that causes ‘the flu’ – (runny nose, sore throat, coughing, and fatigue) – with the symptom arising two days after exposure and lasting for about a week. In humans, there are three types of influenza viruses, called Type A, Type B, and Type C. Type A are the most virulent in humans. The influenza virus behind both of the outbreaks in the 1918 pandemic was a Type A.
Schematic of Influenza virus. Source: Bcm
As the image above indicates, the influenza virus has a rounded shape, with “HA” (hemagglutinin) and “NA” (neuraminidases) proteins on the outer surface of the virus. The HA protein allows the virus to stick to the outer membrane of a cell. The virus can then infect the host cell and start the process of reproduction – making more copies of itself. The NA protein is required for the virus to exit the host cell and go on to infect other cells. Different influenza viruses have different combinations of hemagglutinin and neuraminidase proteins, hence the numbering. For example, the Type A virus that caused the outbreaks in the 1918 pandemic was called H1N1.
Inside the influenza virus, there are there are eight pieces (segments) of RNA, hence the fact that influenza is an RNA virus. Some viruses have DNA while others have RNA. The 8 segments of RNA provide the information that is required for making new copies of the virus. Each of these segments provides the instructions for making one or more proteins of the virus (eg. segment 4 contains the instructions to make the HA protein).
The 8 segments of RNA in influenza. Source: URMC
The Influenza virus is one of the most changeable viruses we are aware of, which makes it such a tricky beast to deal with. Influenza uses two techniques to change over time. They are called shift and drift.
Shifting is an sudden change in the virus, which produces a completely new combination of the HA and NA proteins. Virus shift can take place when a person or animal is infected with two different subtypes of influenza. When new viral particles are generated inside the cell, there is a mix of both subtypes of virus which gives rise to an all new type of virus.
An example of viral shift. Source: Bcm
Drifting is the process of random genetic mutation. Gradual, continuous, spontaneous changes that occur when the virus makes small “mistakes” during the replication of its RNA. These mistakes can results in a slight difference in the HA or NA proteins, and although those changes are small, they can be significant enough that the human immune system will no longer recognise and attack the virus. This is why you can repeatedly get the flu and why flu vaccines must be administered each year to combat new forms of circulating influenza virus.
What is a flu jab exactly?
Seasonal flu vaccination is a treatment that is given each year to minimise the risk of being infected by an influenza virus.
The ‘seasonal’ part of the label refers to the fact that the flu vaccine changes each year. Most flu vaccines target three strains of the viruses (and are thus called ‘Trivalent flu vaccines’) which are selected each year based on data collected by various health organisations around the world.
The three chosen viruses for a particular year are traditionally injected into and grown in hens’ eggs, then harvested and purified before the viral particles are chemically deactivated. The three dead viruses are then pooled together and packaged as a vaccine. As you can see in the image below, the process of vaccine production is laborious and takes a full year:
The process of vaccine production. Source: Linkedin
By injecting people with the dead viruses from three different strains of the influenza virus, however, the immune system has the chance to build up a defence against those viruses without the risk of the individual becoming infected (the dead viruses in the vaccine can not infect cells).
Flu vaccines cause the immune system to produce antibodies which are used by the immune system to help defend the body against future attacks from viruses. These antibodies generally take about two weeks to develop in the body after vaccination.
As we have said most injected flu vaccines protect against three types of flu virus. Generally each of the three viruses is taken from the following strains:
- Influenza A (H1N1) – the strain of flu that caused the swine flu pandemic in 2009.
- Influenza A (H3N2) – a strain of flu that mainly affects the elderly and people at risk with long term health conditions. In 2016/17 the vaccine contains an A/Hong Kong/4801/2014 H3N2-like virus.
- Influenza B – a strain of flu that particularly affects children. In 2016/17 the vaccine contains B/Brisbane/60/2008-like virus.
How effective are the vaccines?
Well, it really depends on which strains of influenza are going to affect the most people each year, and this can vary greatly. Overall, however, research from the Centers for Disease Control and Prevention (or CDC) suggests that the seasonal flu vaccine reduces the chance of getting sick by approximately 50% (Source). Not bad when you think about it.
Ok, so are there actually any connections between influenza and Parkinson’s disease?
This question is up for debate.
There are certainly some tentative associations between influenza and Parkinson’s disease. Early on, those connections were coincidental, but more recently research is suggesting that there could be a closer relationship.
Between January 1918 and December 1920 there were two outbreaks of an influenza virus during an event that became known as the 1918 flu pandemic. Approximately 500 million people across the globe were infected by the H1N1 influenza virus, and this resulted in 50 to 100 million deaths (basically 3-5% of the world’s population). Given that is occurred during World War 1, censors limited the media coverage of the pandemic in many countries in order to maintain morale. The Spanish media were not censored, however, and this is why the 1918 pandemic is often referred to as the ‘Spanish flu’.
1918 Spanish flu. Source: Chronicle
At the same time that H1N1 was causing havoc, a Romanian born neurologist named Constantin von Economo reported a number of unusual symptoms which were referred to as encephalitis lethargica (EL). This disease left victims in a statue-like condition, speechless and motionless.
Constantin von Economo. Source: Wikipedia
By 1926, EL had spread around the world, with nearly five million people being affected. Many of those who survived never returned to their pre-existing state of health. They were left frozen in an immobile state.
An individual with encephalitis lethargica. Source: Baillement
Historically, it was believed that EL was caused by the influenza virus from the 1918 Spanish influenza pandemic. This was largely due to a temporal association (things happening at approximately the same time) and the finding of influenza antigens in some of the suffers of EL (Click here to read more about this).
And then there were also the observations of Dr Oliver Sacks:
Amazing guy! Dr Oliver Sacks. Source: Pensologosou
During the late 1960s, while employed as a neurologist at Beth Abraham Hospital’s chronic-care facility in New York, Dr Sacks began working with a group of survivors of EL, who had been left immobile by the condition. He treated these individuals with L-dopa (the standard treatment for Parkinson’s disease now, but it was still experimental at the time) and he observed them become miraculously reanimated. The sufferers went from being completely motionless to suddenly active and mobile. Unfortunately the beneficial effects were very short lived.
You may be familiar with Dr Sack’s book about his experience of treating these patients. It is called ‘Awakenings’ and it was turned into a film starring actors Robin Williams and Robert De Niro.
Robin Williams and Robert De Niro in Awakenings. Source: Pinterest
More recent, postmortem analysis of the brains of EL patients found an absence of influenza RNA – click here for more on this), which has led many researchers to simply reject the association between influenza and EL. The evidence supporting this rejection, however, has also been questioned (click here to read more on this), leaving the question of an association between influenza and EL still open for debate.
I think it’s fair to say that we genuinely do not know what caused EL. Whether it was influenza or not is still be undecided.
Ok, so that was the coincidental evidence. Has there been a more direct connection between influenza and Parkinson’s disease?
This is Dr Richard J Smeyne:
He is a research faculty member in the Department of Developmental Neurobiology at St. Jude Children’s Research Hospital (Memphis, Tennessee).
He has had a strong interest in what role viruses like influenza could be playing in the development of Parkinson’s disease, and his research group has published several interesting research reports on this topic, including:
Title: Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration.
Author: Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ.
Journal: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8.
PMID: 19667183 (This article is OPEN ACCESS if you would like to read it)
Dr Smeyne and his colleagues found in this study that when they injected the highly infectious A/Vietnam/1203/04 (H5N1) influenza virus into mice, the virus progressed from the periphery (outside the brain) into the brain itself, where it induced Parkinson’s disease-like symptoms.
The virus also caused a significant increase in the accumulation of the Parkinson’s disease-associated protein Alpha Synuclein. In addition, they witnessed the loss of dopamine neurons in the midbrain of the mice at 60 days after the infection – that cell loss resembling what is observed in the brains of people with Parkinson’s disease.
Naturally this got the researchers rather excited!
In a follow up study on H5N1, however, these same researchers found that the Parkinson’s disease-like symptoms that they observed were actually only temporary:
Title: Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice.
Authors: Jang H, Boltz D, McClaren J, Pani AK, Smeyne M, Korff A, Webster R, Smeyne RJ.
Journal: Journal for Neuroscience, 2012 Feb 1;32(5):1545-59.
PMID: 22302798 (This article is OPEN ACCESS if you would like to read it)
Dr Smeyne and colleagues repeated the 2009 study and had a closer look at what was happening to the dopamine neurons that were disappearing at 60 days post infection with the virus. When they looked at mice at 90 days post infection, they found that the number of dopamine neurons had returned to their normal number. This pattern was also observed in a region of the brain called the striatum, where the dopamine neurons release their dopamine. The levels of dopamine dropped soon after infection, but rose back to normal by 90 days post infection.
How does that work?
The results suggest that rather than developing new dopamine neurons in some kind of miraculous regenerative process, the dopamine neurons that were infected by the virus simply stopped producing dopamine while they dealt with the viral infection. Once the crisis was over, the dopamine neurons went back to life as normal. And because the researcher use chemicals in the production of dopamine to identify the dopamine neurons, they mistakenly thought that the cells had died when they couldn’t see those chemicals.
One interesting observation from the study was that H5N1 infection in mice induced a long-lasting inflammatory response in brain. The resident helper cells, called microglia, became activated by the infection, but remained active long after the dopamine neurons returned to normal service. The investigators speculated as to whether this activation may be a contributing factor in the development of neurodegenerative disorders.
And this is an interesting idea.
In a follow up study, they investigated this further by looking another influenza viruse that doesn’t actually infect cells in the brain:
Title: Induction of microglia activation after infection with the non-neurotropic A/CA/04/2009 H1N1 influenza virus.
Author: Sadasivan S, Zanin M, O’Brien K, Schultz-Cherry S, Smeyne RJ.
Journal: PLoS One. 2015 Apr 10;10(4):e0124047.
PMID: 25861024 (This article is OPEN ACCESS if you would like to read it)
In this study, a different type of influenza (H1N1) was tested, and while it did not infect the brain, it did cause the microglia cells to flare up and become activated. And again, this activation was sustained for a long period after the infection (at least 90 days).
This is a really interesting finding and relates to the idea of a “double hit” theory of Parkinson’s disease, in which the virus doesn’t necessarily cause Parkinson’s disease but may play a supplemental or distractionary role, grabbing the attention of the immune system while some other toxic agent is also attacking the body. Or perhaps simply weakening the immune system by forcing it to fight on multiple fronts. Alone the two would not cause as much damage, but in combination they could deal a terrible blow.
So what was the flu vaccine research published last week?
Again, from Dr Smeyne’s research group, this report looked whether the combination of an influenza virus infection plus a toxic agent gave a worse outcome than just the toxic agent by itself. An interesting idea for a study, but then the investigators threw in another component: what effect would a influenza vaccine have in such an experiment. And the results are interesting:
Title: Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis
Authors: Sadasivan S, Sharp B, Schultz-Cherry S, & Smeyne RJ
Journal: npj Parkinson’s Disease 3, 18
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
What the researchers found was that H1N1-infected mice that were treated with a neurotoxin (called MPTP – a toxin that specifically kills dopamine neurons) exhibit a 20% greater loss of dopamine neurons than mice that were treated with MPTP alone.
And this increase in dopamine neuron loss was completely eliminated by giving the mice the influenza vaccination. The researchers concluded that the results demonstrate that multiple insults (such as a viral infection and a toxin) can enhance the impact, and may even be significant in allowing an individual to cross a particular threshold for developing a disease.
It’s an intriguing idea.
Have epidemiologists (population data researchers) ever investigated a connection between Parkinson’s disease and influenza?
And yes they have:
Title: Parkinson’s disease or Parkinson symptoms following seasonal influenza.
Authors: Toovey S, Jick SS, Meier CR.
Journal: Influenza Other Respir Viruses. 2011 Sep;5(5):328-33.
PMID: 21668692 (This article is OPEN ACCESS if you would like to read it)
In this first study, the researcher used the UK‐based General Practice Research Database to perform a case–control analysis (that means they compare an affected population with an unaffected ‘control’ population. They identified individual cases who had developed an ‘incident diagnosis’ of Parkinson’s disease or Parkinson’s like symptoms between 1994 and March 2007. For each of those case files identified, they matched them with at least four age matched control case files for comparative sake.
Their analysis found that the risk of developing Parkinson’s disease was not associated with previous influenza infections. BUT, they did find that Influenza was associated with Parkinson’s‐like symptoms such as tremor, particularly in the month after an infection. One can’t help but wonder if the dopamine neurons stopped producing dopamine during that period while they dealt with the viral infection.
But of course, I’m only speculating here… and it’s not like there was a second study suggesting that there is actually an association between Parkinson’s disease and influenza.
A year after that first study, a second study was published:
Journal: Association of Parkinson’s disease with infections and occupational exposure to possible vectors.
Authors: Harris MA, Tsui JK, Marion SA, Shen H, Teschke K.
Journal: Movement Disorder. 2012 Aug;27(9):1111-7.
This second study reported that there is actually an association between Parkinson’s disease and influenza.
This investigation was also a case-control study, but it was based in British Columbia, Canada. The researchers recruited 403 individuals detected by their use of antiparkinsonian medications and matched them with 405 control subjects selected from the universal health insurance plan. Severe influenza was associated with Parkinson’s disease at an odds ratio of 2.01 (1 being no difference) and the range of the odds was 1.16-3.48. That’s pretty significant.
Interestingly, the effect is reduced when the reports of infection were restricted to those occurring within 10 years before diagnosis. This observation would suggest that early life infections may have more impact than previously thought.
Curiously, the researchers also found that exposure to certain animals (cats odds ration of 2.06; range 1.09-3.92) and cattle (2.23; range 1.22-4.09) was also associated with developing Parkinson’s disease.
Time to get rid of the pet cow.
Do any other neurodegenerative condition have associations with influenza?
In the limited literature search that we conducted, we only found reports dealing with influenza and Alzheimer’s disease.
Large studies suggest that Alzheimer’s is not associated with influenza (click here to read more on this). Interestingly, the Alzheimer’s associated protein beta amyloid has been shown to inhibit influenza A viruses (Click here to read that report), which may partly explain the lack of any association.
Influenza does have a mild association, however, with depression (Click here to see that report).
So what does it all mean?
A viral theory for Parkinson’s disease has existed since the great epidemic of 1918. Recent evidence points towards several viruses potentially having some involvement in the development of this neurodegenerative condition. And recent evidence suggests that influenza in particular could be particularly influential.
In 1938, Jonas Salk and Thomas Francis developed the first vaccine against flu viruses. It could be interesting for epidemiologists to go back and see if regular flu vaccination usage (if such data exists) reduces the risk of developing Parkinson’s disease.
But until such data is published, however, perhaps it would be wise to go and get a flu vaccine shot.
The banner for today’s post was sourced from the HuntingtonPost
I was recently made aware of an interesting fact:
Approximately 5% of people with Human immunodeficiency virus (HIV) infections develop Parkinson’s disease-like features.
Why is this?
In today’s post we will try to understand what is going on, and what it may mean for Parkinson’s disease.
HIV (in green) budding (being released) from a blood cell (lymphocyte). Source: Wikipedia
Ok, let’s start at the beginning:
What is HIV?
Human immunodeficiency virus (or HIV) – as the name suggests – is the virus.
It causes the infection which gives rise to Acquired Immune Deficiency Syndrome (or AIDS). AIDS is a progressive failure of the immune system – the body loses its ability to fight infections. Without treatment, average survival period after infection with HIV is between 9 – 12 years.
HIV can be spread by the transfer of bodily fluids, such as blood and semen. The World Health Organisation (WHO) has estimated that approximately 36.9 million people worldwide were living with HIV/AIDS at the end of 2014 (that is equivalent to the entire population of Canada!).
The structure of the HIV virus. Source: Wikipedia
Does HIV affect the brain?
At postmortem examinations, less than 10% of the brains from HIV infected individuals are histologically normal (Source).
HIV is a member of the lentivirus family of viruses, which readily infect immune cells (such as blood cells). HIV can also infect other types of cells though, including those in the brain. HIV will usually enter the central nervous system within the first month following infection. It enters the brain via infected blood cells which come into contact with brain ‘immune system/helper’ cells such as microglia and macrophages at the blood-brain-barrier.
How HIV enters the brain. Source: Disease Models and Mechanisms
HIV can also infect astrocytes (albeit at a lower frequency than microglia and macrophages), by direct cell-cell contact with infected T cells (blood cells) at the blood-brain-barrier (No. 1 in the image above). After infecting astrocytes, there is dysfunction in the astrocyte and it will no longer be so supportive to the local neurons (No. 2 in the image above). Once inside the brain, HIV-infected macrophages will allow for infection of other macrophages and microglia (No. 3 in the image above), and all together these HIV-infected astrocytes and microglia will cause damage to neurons by releasing viral proteins (two in particular, called Tat and gp120) and additional nasty chemicals which are bad for the neurons (No. 4 in the image above). Finally, as the disease progresses, the protective layer of the blood-brain-barrier becomes compromised and HIV-infected T cells eventually enter the brain and they cause damage to neurons by releasing pro-inflammatory chemicals (making the environment harsh for neurons).
There is remarkably little evidence of HIV actually infecting neurons (Click here for a review on this), so any cell loss in the brain that is associated with HIV does not result from neurons themselves being infected. This may be due to the fact that neurons do not have the HIV receptors (such as CD4) on their cell membrane. Similarly, oligodendrocytes (a supporting cell) does not appear to be easily infected by HIV. The bulk of the infected cells in the brain appear to be of the microglial, macrophage and astrocytes. And without these supporting cells doing their jobs in a normal fashion, it is easy to see how neurons can start dying off.
The severity, characteristics and distribution of HIV-induced injury in the brain varies greatly between affected individuals. It is most likely associated with the viral load (or the number of viral particles) in the brain, which can vary from a few thousand to more than a million copies per mL.
Do HIV-infected people show any signs of the virus entering the brain?
For the majority of people infected with HIV, this entry of the virus into the nervous system is neurologically asymptomatic (meaning they will not notice it), except for the occasional mild headache (for more on this read this review). As a result of the HIV virus entering the brain, however, many infected individuals will suffer from a specific set of neurological disorders, collectively called the AIDS dementia complex (ADC) (also known as HIV-associated cognitive/motor complex, or simply HIV dementia).
So how does HIV infection result in Parkinson’s disease-like features?
As we have suggested in the introduction to this post, on rare occasions (approximately 5% of cases), HIV-infected patients may present an illness virtually identical to Parkinson’s disease. More commonly, people with HIV will exhibit an increased sensitivity to dopamine receptor-blocking agents, such as drugs with a low potential for inducing Parkinsonism, (for example prochlorperazine and metoclopropamide).
The exact mechanism by which HIV infection results in Parkinson’s disease-like features is the subject of debate, but what is clear is that the basal ganglia (a structure involved in Parkinson’s disease) faces the brunt of the HIV infection in the brain. HIV-infected microglia and macrophage are most prominent in the basal ganglia when compared to other brain regions (Click here and here for more on this), and the basal ganglia is where the chemical dopamine from the midbrain is being released.
In addition, there are other changes in the brains of HIV infected people which may aid in the appearance of Parkinsonian features:
Title: Increased frequency of alpha-synuclein in the substantia nigra in human immunodeficiency virusinfection.
Authors: Khanlou N, Moore DJ, Chana G, Cherner M, Lazzaretto D, Dawes S, Grant I, Masliah E, Everall IP; HNRC Group.
Journal: J Neurovirol. 2009 Apr;15(2):131-8.
PMID: 19115126 (This article is OPEN ACCESS if you would like to read it)
The researchers in this study used staining techniques to look at the amount of alpha synuclein – the Parkinson’s associated protein – in slices of brain tissue taken from postmortem autopsies of 73 HIV+ individuals aged between 50 and 76 years of age.
The presence of alpha synuclein in the substantia nigra (an area of the brain affected by Parkinson’s disease) was a lot higher in the HIV+ brains when compared with healthy control samples (16% of the HIV+ brains had high levels of alpha synclein vs 0% for the healthy brains).
Interestingly, nearly all of the brains analysed (35 out of 36 HIV+ brains) had high levels of the Alzheimer’s disease associated protein, beta amyloid (which again raises the question of whether beta amyloid could be playing a defensive role in infections – see our previous post on this). Also interesting, was that there was no correlation between these proteins being present and the age of the person at death – that is to say, older brains did not have more of these proteins when compared with younger brains.
There are also additional ways in which HIV could be causing Parkinson’s-like features, such as:
- HIV has been shown to affect the protein levels of Parkinson’s disease associated proteins, such as DJ1 and Lrrk2 (Click here and here to read more on this).
- HIV can, in some cases, increase the level of Dopamine transporter, which would reduce the levels of free floating dopamine in the brain (Click here to read more about this).
How is HIV treated?
Treating HIV. Source: NPR
There is currently no cure for HIV infection.
There are, however, treatments which help to slow the virus down. These are called Anti-retroviral drugs (HIV is a retrovirus). There are different kinds of anti-retroviral drugs, which act at different stages of the HIV life cycle. Combinations of several anti-retroviral drugs (generally three or four) is known as ‘Highly Active Anti-Retroviral Therapy'(or HAART).
Mechanism by which four classes of anti-retroviral drugs work against HIV. Source: Wikipedia
As the schematic image above highlights, there are many ways to slow down the HIV virus. For example, you can prevent it from attaching to a cell and fusing with the cell membrane (fusion inhibitors). By treating HIV infected people with multiple medications attacking different parts of the HIV life cycle, the virus has been slowed down.
Does HAART treatments for HIV help with these Parkinson’s-like features?
In some cases, the answer appears to be yes.
There are numerous case studies in the literature which demonstrate the alleviation of HIV-associated Parkinsonian symptoms with HAART, such as this report:
Title: Parkinsonism as the presenting manifestation of HIV infection: improvement on HAART.
Authors: Hersh BP, Rajendran PR, Battinelli D.
Journal: Neurology. 2001 Jan 23;56(2):278-9.
In this study the researchers described the case of a 37 year old man who developed Parkinson’s like features in the setting of an HIV infection, which were resolved after 1 year of HAART.
Over a period of 4 months, the man developed co-ordination issue, clumsiness and an irregular tremor in his right hand (there was, however, no resting tremor). He noted a generalised slowness and exhibited a tendency towards decreased right arm swinging. He also developed dystonia in the right hand/arm. Following L-dopa treatment (25/100; one tablet 3x per day) there was improvement in balance & co-ordination, speech, facial expression, and the tremor (L-dopa does appear to improve most cases of HIV-associated Parkinson’s-like features).
Six months after first displaying these Parkinsonian features (and two month after initiating L-dopa treatment), the subject was placed on HAART treatment. Four months later, he discontinued L-dopa treatment and 12 months after starting the HAART regime his Parkinsonian features were largely resolved.
What does this mean for Parkinson’s disease?
This post was written for the research community rather than people with Parkinson’s disease. I thought the fact that some people with HIV can start to have Parkinson’s like features was an interesting curiosity and wanted to share/spread the information.
Having said that, this post raises some really interesting questions, such as if a virus like HIV can have this effect on the brain, could other viruses be having similar effects? Could some cases of Parkinson’s disease simply be the result of a viral infection? Either multiple hits from a particular virus or different viruses each taking a varying toll over the course of a life time.
This idea would explain many of the curious features of Parkinson’s disease, such as:
- the asymmetry of the symptoms (people with Parkinson’s usually have the disease starting on one side of the body.
- the fact that some cells in the brain are more vulnerable to the disease than others (perhaps they are more receptive to a particular virus).
- the protein clusterings in the cells (Lewy bodies may be defensive efforts against viral infections).
As we have previous mentioned, theories of viral causes for Parkinson’s have been circulating ever since the 1918 flu pandemic (Click here to read our previous post on this topic). About the same time as the influenza virus was causing havoc around the world, another condition began to appear called ‘encephalitis lethargica‘. This disease left many of the victims in a statue-like condition, both motionless and speechless – similar to Parkinson’s disease. Initially, it was assumed that the influenza virus was the causal factor, but more recent research has left us not so sure anymore.
The point is, however, perhaps it is time for us to re-examine the possibility of a viral agent being involved in the development of Parkinson’s disease.
There is new technology that allows us to determine the viral history of each individual from a simple blood test (Click here for more on this), so it would be interesting to compare blood samples from people with Parkinson’s disease with healthy controls to determine any differences.
In addition to the overall question of a viral role in Parkinson’s disease, there also remains the question of why only a small fraction of people with HIV are affected by Parkinsonisms. It could be interesting to genetically screen those people with HIV that exhibit Parkinsonisms and compare them with people with HIV that do not. Do those affected individuals have recognised Parkinson’s related genetic mutations? Or do they have novel genetic variations that could tell us more about Parkinson’s disease?
Food for thought. Would be happy to hear others thoughts.
The banner for today’s post was sourced from AidsServices