Gene therapy involves treating medical conditions at the level of DNA – that is, altering or enhancing the genetic code inside cells to provide therapeutic benefits rather than simply administering drugs. Usually this approach utilises specially engineered viruses to deliver the new DNA to particular cells in the body.
For Parkinson’s, gene therapy techniques have all involved direct injections of these engineered viruses into the brain – a procedure that requires brain surgery. This year, however, we have seen the EXTREMELY rapid development of a non-invasive approach to gene therapy for neurological condition, which could ultimately see viruses being injected in the arm and then travelling up to the brain where they will infect just the desired population of cells.
Last week, however, this approach hit a rather significant obstacle.
In today’s post, we will have a look at this gene therapy technology and review the new research that may slow down efforts to use this approach to help to cure Parkinson’s.
Gene therapy. Source: rdmag
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 begun to see more and more 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.
A good 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 – 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?
One of the cardinal features of the Parkinsonian brain are dense, circular clusters of protein that we call ‘Lewy bodies’.
But what exactly are these Lewy bodies?
How do they form?
And what function do they serve?
More importantly: Are they part of the problem – helping to cause of Parkinson’s? Or are they a desperate attempt by a sick cell to save itself?
In today’s post, we will have a look at new research that makes a very close inspection of Lewy bodies and finds some interesting new details that might tell us something about Parkinson’s.
Neuropathologists conducting a gross examination of a brain. Source: NBC
A definitive diagnosis of Parkinson’s disease can only be made at the postmortem stage with an examination of the brain. Until that moment, all cases of Parkinson’s disease are ‘suspected’.
When a neuropathologist makes an examination of the brain of a person who passed away with the clinical features of Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a final diagnosis of the condition:
1. The loss of specific populations of cells in the brain, such as the dopamine producing neurons in a region called the substantia nigra, which lies in an area called the midbrain (at the base of the brain/top of the brain stem).
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp
2. Dense, circular clusters (or aggregates) of protein within cells, which are called Lewy bodies.
A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news
What is a Lewy body?
A Lewy body is referred to as a cellular inclusion (that is, ‘a thing that is included within a whole’), as they are almost always found inside the cell body. They generally measure between 5–25 microns in diameter (5 microns is 0.005 mm) thus they are tiny, but when compared to the neuron within which they reside they are rather large (neurons usually measures 40-100 microns in diameter).
A photo of a Lewy body inside of a neuron. Source: Neuropathology-web
How do Lewy bodies form? And what is their function?
The short answer to these questions is:
The longer answer is: Our understanding of how Lewy bodies are formed – and their actual role in neurodegenerative conditions like Parkinson’s – is extremely limited. No one has ever observed one forming. Lewy bodies are very difficult to generate in the lab under experimental conditions. And as for their function, this is the source of much guess work and serious debate (we’ll come back to this topic later in this post).
Ok, but what are Lewy bodies actually made of?
Last year – two years after actor Robin Williams died – his wife Susan Schneider Williams wrote an essay entitled The terrorist inside my husband’s head, published in the journal Neurology.
It is a heartfelt/heartbreaking insight into the actor’s final years. It also highlights the plight of many who are diagnosed with Parkinson’s disease, but experience an array of additional symptoms that leave them feeling that something else is actually wrong.
Today’s post is all about Dementia with Lewy bodies (or DLB). In particular, we will review the latest refinements and recommendations of the Dementia with Lewy Bodies Consortium, regarding the clinical and pathologic diagnosis of DLB.
Robin Williams. Source: Quotesgram
On the 28th May of 2014, the actor Robin Williams was diagnosed with Parkinson’s disease.
At the time, he had a slight tremor in his left hand, a slow shuffling gait and mask-like face – some of the classical features of Parkinson’s disease.
According to his wife, the diagnosis gave the symptoms Robin had been experiencing a name. And this brought her a sense of relief and comfort. Now they could do something about the problem. Better to know what you are dealing with rather than be left unsure and asking questions.
But Mr Williams sensed that something else was wrong, and he was left unsure and asking questions. While filming the movie Night at the Museum 3, Williams experienced panic attacks and regularly forgot his lines. He kept asking the doctors “Do I have Alzheimer’s? Dementia? Am I schizophrenic?”
Williams took his own life on the 11th August 2014, and the world mourned the tragic loss of a uniquely talented performer.
When the autopsy report came back from the coroner, however, it indicated that the actor had been misdiagnosed.
He didn’t have Parkinson’s disease.
What he actually had was Dementia with Lewy bodies (or DLB).
What is Dementia with Lewy bodies?
The contents of today’s post may not be appropriate for all readers. An illegal and potentially damaging drug is discussed. Please proceed with caution.
3,4-Methylenedioxymethamphetamine (or MDMA) is more commonly known as Ecstasy, ‘Molly’ or simply ‘E’. It is a controlled Class A, synthetic, psychoactive drug that was very popular with the New York and London club scene of the 1980-90s.
It is chemically similar to both stimulants and hallucinogens, producing a feeling of increased energy, pleasure, emotional warmth, but also distorted sensory perception.
Another curious effect of the drug: it has the ability to reduce dyskinesias – the involuntary movements associated with long-term Levodopa treatment.
In today’s post, we will (try not to get ourselves into trouble by) discussing the biology of MDMA, the research that has been done on it with regards to Parkinson’s disease, and what that may tell us about dyskinesias.
Good times. Source: Carwash
You may have heard this story before.
It is about a stuntman.
His name is Tim Lawrence, and in 1994 – at 34 years of age – he was diagnosed with Parkinson’s disease.
Tim Lawrence. Source: BBC
Following the diagnosis, Tim was placed on the standard treatment for Parkinson’s disease: Levodopa. But after just a few years of taking this treatment, he began to develop dyskinesias.
Dyskinesias are involuntary movements that can develop after regular long-term use of Levodopa. There are currently few clinically approved medications for treating this debilitating side effect of Levodopa treatment. I have previously discussed dyskinesias (Click here and here for more of an explanation about them).
As his dyskinesias progressively got worse, Tim was offered and turned down deep brain stimulation as a treatment option. But by 1997, Tim says that he spent most of his waking hours with “twitching, spasmodic, involuntary, sometimes violent movements of the body’s muscles, over which the brain has absolutely no control“.
And the dyskinesias continued to get worse…
…until one night while he was out at a night club, something amazing happened:
“Standing in the club with thumping music claiming the air, I was suddenly aware that I was totally still. I felt and looked completely normal. No big deal for you, perhaps, but, for me, it was a revelation” he said.
His dyskinesias had stopped.
In 2002, deep brain stimulation (or DBS) was granted approval for the treatment of Parkinson’s disease by the US Food and Drug Administration (FDA). The historical starting point for this technology, however, dates quite far back…
Further back than many of you may be thinking actually…
In his text “Compositiones medicamentorum” (46 AD), Scribonius Largo, head physician of the Roman emperor Claudius, first suggested using pulses of electricity to treat afflictions of the mind.
Roman emperor Claudius. Source: Travelwithme
He proposed that the application of the electric ray (Torpedo nobiliana) on to the cranium could be a beneficial remedy for headaches (and no, I’m not kidding here – this was high tech at the time!).
Torpedo nobiliana. Source: Wikipedia
These Atlantic fish are known to be very capable of producing an electric discharge (approximately 200 volts). The shock is quite severe and painful – the fish get their name from the Latin “torpere,” meaning to be stiffened or paralysed, referring specifically to the response of those who try to pick these fish up – but the shock is not fatal.
Now, whether Largo was ever actually allowed to apply this treatment to the august ruler is unknown, and beyond the point. What matters here is that physicians have been considering and using this approach for a long time. And more recently, the application of it has become more refined.
What is deep brain stimulation?
The modern version of deep brain stimulation is a surgical procedure in which electrodes are implanted into the brain. It is used to treat a variety of debilitating symptoms, particularly those associated with Parkinson’s disease, such as tremor, rigidity, and walking problems.
For many people diagnosed with Parkinson’s disease, one of the scariest prospects of the condition that they face is the possibility of developing dyskinesias.
Dyskinesias are involuntary movements that can develop after long term use of the primary treatment of Parkinson’s disease: Levodopa
In todays post I discuss one experimental strategy for dealing with this debilitating aspect of Parkinson’s disease.
Dyskinesia. Source: JAMA Neurology
There is a normal course of events with Parkinson’s disease (and yes, I am grossly generalising here).
First comes the shock of the diagnosis.
This is generally followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial).
Then comes the period during which one will try to familiarise oneself with the condition (reading books, searching online, joining Facebook groups), and this usually leads to awareness of some of the realities of the condition.
One of those realities (especially for people with early onset Parkinson’s disease) are dyskinesias.
What are dyskinesias?
Dyskinesias (from Greek: dys – abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterised by involuntary muscle movements. And they are certainly not specific to Parkinson’s disease.
As I have suggested in the summary at the top, they are associated in Parkinson’s disease with long-term use of Levodopa (also known as Sinemet or Madopar).
Sinemet is Levodopa. Source: Drugs
Being a proud kiwi, I am happy to highlight and support any research coming out of New Zealand.
Recently a new commentary has been published suggesting that living in the NZ city of Rotorua (‘Roto-Vegas‘ to the locals) may decrease the risk of developing Parkinson’s disease.
In today’s post, we will review the research behind the idea and discuss what it could mean for people with neurodegenerative conditions, like Parkinson’s disease.
The geothermal wonderlands of Rotorua. Source: Audleytravel
Rotorua is a small city in the central eastern area of the North Island of New Zealand (Aotearoa in the indigenous Māori language).
The name Rotorua comes from the Māori language (‘roto’ meaning lake and rua meaning ‘two’). The full Māori name for the spot is actually Te Rotorua-nui-a-Kahumatamomoe. The early Māori chief and explorer Ihenga named it after his uncle Kahumatamomoe. But given that it was the second major lake found in Aotearoa (after lake Taupo in the centre of the North Island), the name that stuck was Rotorua or ‘Second lake’.
Maori culture. Source: TamakiMaoriVillage
Similar to lake Taupo, Rotorua is a caldera resulting from an ancient volcanic eruption (approximately 240,000 years ago). The lake that now fills it is about 22 km (14 mi) in diameter.
Lake Rotorua. Source: Teara
The volcano may have disappeared, but the surrounding region is still full of geothermal activity (bubbling mud pools and geysers), providing the region with abundant renewable power and making the city a very popular tourist destination.
Tourist playing with mud. Source: Rotoruanz
Before visiting the city, however, travellers should be warned that Rotorua’s other nicknames include “Sulphur City” and “Rotten-rua”, because of the smell that results from the geothermal activity.
And speaking from personal experience, the “rotten eggs” smell is prevalent.
Interesting, but what has this got to do with the science of Parkinson’s disease?
Well, the rotten egg smell is the result of hydrogen sulfide emissions, and recently it has been suggested that this pungent gas may be having positive benefits on people, particularly with regards to Parkinson’s disease.
This idea has been proposed by Dr Yusuf Cakmak at the University of Otago in a recent commentary:
Title: Rotorua, hydrogen sulphide and Parkinson’s disease-A possible beneficial link?
Author: Cakmak Y.
Journal: N Z Med J. 2017 May 12;130(1455):123-125.
In his write up, Dr Cakmak points towards two studies that have been conducted on people from Rotorua. The first focused on examining whether there was any association between asthma and chronic obstructive pulmonary disease and exposure to hydrogen sulfide in Rotorua. By examining air samples and 1,204 participants, the investigators of that study no association (the report of that study is OPEN ACCESS and can be found by clicking here).
The second study is the more interesting of the pair:
Title: Chronic ambient hydrogen sulfide exposure and cognitive function.
Authors: Reed BR, Crane J, Garrett N, Woods DL, Bates MN.
Journal: Neurotoxicol Teratol. 2014 Mar-Apr;42:68-76.
PMID: 24548790 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators recruited 1,637 adults (aged 18-65 years) from Rotorua. They conducted neuropsychological tests on the subjects, measuring visual and verbal episodic memory, attention, fine motor skills, psychomotor speed and mood. The average amount of time the participants had lived in the Rotorua region was 18 years (ranging from 3-64 years). The researchers also made measurements of hydrogen sulfide levels at the participants homes and work sites.
While the researchers found no association between hydrogen sulfide exposure and cognitive ability, they did notice something interesting in the measures of fine motor skills: individuals exposed to higher levels of hydrogen sulfide displayed faster motor response times on tasks like finger tapping. Finger tapping speed is an important part of Parkinson’s Motor Rating Scale examination tests.
The investigators behind the study concluded that the levels of hydrogen sulfide in Rotorua do not have any detrimental effect on the individuals living in the area,
Dr Cakmak, however, wondered whether “relatively high, but safe, hydrogen sulfide levels in Rotorua could help protect the degradation of dopaminergic neurons associated with Parkinson’s Disease?” (based on the better performance on the motor response time).
Hang on a second, what exactly is hydrogen sulfide?
Hydrogen sulfide (chemical symbol: H2S) is a colourless gas. Its production often results from the the breaking down of organic material in the absence of oxygen, such as in sewers (this process is called anaerobic digestion. It also occurs in volcanic and geothermal conditions.
H2S. Source: Wikipedia
About 15 years ago, it was found in various organs in the body and termed a gasotransmitter. A gasotransmitter is a molecule that can be used to transmit chemical signals from one cell to another, which results in certain physiological reactions (oxygen, for example, is a gasotransmitter).
Hydrogen sulfide is now known to be cardioprotective (protection of the heart), and many years of research have demonstrated beneficial aspects of using it in therapy, such as vasodilation and lowering blood pressure, increasing levels of antioxidants, inhibiting inflammation, and activation of anti-apoptotic (anti-cell death) pathways. For a good review of hydrogen sulfide’s cardioprotective properties – click here.
The demonstration of the protective properties of hydrogen sulfide in other bodily organs have led neuroscientists to start investigating whether these same benefits could be utilised in treating disorders of the brain.
And the good news is: hydrogen sulfide can have positive benefits in the brain – Click here for a good review of the brain-related research.
Has other research been conducted on hydrogen sulfide regarding Parkinson’s disease?
Yes. And here is where the story starts to get really interesting.
Then hydrogen sulfide was tested in rodent models of Parkinson’s disease:
Title: Neuroprotective effects of hydrogen sulfide on Parkinson’s disease rat models.
Authors: Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS.
Journal: Aging Cell. 2010 Apr;9(2):135-46.
PMID: 20041858 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers firstly looked at what happens to hydrogen sulfide in the brains of rodent models of Parkinson’s disease. When rats were injected with a neurotoxin (6-OHDA) that kills dopamine neurons, the investigators found a significant drop in the level of hydrogen sulfide in the region where the dopamine cells reside (called the substantia nigra – an area of the brain severely affected in Parkinson’s disease).
Next the researchers gave some rodents the neurotoxin, waited three weeks and then began administering sodium hydrosulfide – which is a hydrogen sulfide donor – every day for a further 3 weeks. They found that this treatment significantly reduced the dopamine cell loss, motor problems and inflammation in the sodium hydrosulfide treated animals. Interestingly, they saw the same neuroprotective effect when they repeated the study with a different neurotoxin (Rotenone). The investigators concluded that hydrogen sulfide “has potential therapeutic value for treatment of Parkinson’s disease”.
And this first study was followed up one year later by a study investigating inhaled hydrogen sulfide:
Title: Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson’s disease.
Authors: Kida K, Yamada M, Tokuda K, Marutani E, Kakinohana M, Kaneki M, Ichinose F.
Journal: Antioxid Redox Signal. 2011 Jul 15;15(2):343-52.
PMID: 21050138 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators gave mice a neurotoxin (MPTP) and then had them breathe air with or without hydrogen sulfide (40 ppm) for 8 hours per day for one week. The mice that inhaled hydrogen sulfide displayed near normal levels of motor behaviour performance and significantly reduced levels of neurodegeneration (dopamine cell loss).
Inhalation of hydrogen sulfide also prevented the MPTP-induced activation of the brain’s helper cells (microglia and astrocytes) and increased levels of detoxification enzymes and antioxidant proteins (including heme oxygenase-1 and glutamate-cysteine ligase). Curiously, hydrogen sulfide inhalation did not significantly affect levels of reduced glutathione (we will come back to this in an upcoming post).
These first two preclinical results have been replicated many times now confirming the initial findings (Click here, here, here and here for examples). The researchers of the second ‘inhalation’ study concluded the study by suggesting that the potential therapeutic effects of hydrogen sulfide inhalation now needed to be examined in more disease relevant models of Parkinson’s disease.
And this is exactly what researchers did next:
Title: Sulfhydration mediates neuroprotective actions of parkin.
Authors: Vandiver MS, Paul BD, Xu R, Karuppagounder S, Rao F, Snowman AM, Ko HS, Lee YI, Dawson VL, Dawson TM, Sen N, Snyder SH.
Journal: Nat Commun. 2013;4:1626. doi: 10.1038/ncomms2623.
PMID: 23535647 (This article is OPEN ACCESS if you would like to read it)
The researchers conducting this study were interested in the interaction of hydrogen sulfide with the Parkinson’s disease-associated protein Parkin (also known as PARK2). They found that hydrogen sulfide actively modified parkin protein – a process called sulfhydration – and that this enhances the protein’s level of activity.
They also noted that the level of Parkin sulfhydration in the brains of patients with Parkinson’s disease is markedly reduced (a 60% reduction). These finding imply that drugs that increase levels of hydrogen sulfide in the brain may be therapeutic.
Interestingly, cells with genetic mutations in another Parkinson’s disease related gene, DJ-1, also produce less hydrogen sulfide (click here to read more about this).
Has anyone ever looked at hydrogen sulfide and alpha synuclein?
Not that we are aware of.
Alpha synuclein is the Parkinson’s disease associated protein that clusters in the Parkinsonian brain and forms Lewy bodies.
But researchers have looked at hydrogen sulfide and amyloid formation:
Title: Hydrogen sulfide inhibits amyloid formation
Authors: Rosario-Alomar MF, Quiñones-Ruiz T, Kurouski D, Sereda V, Ferreira EB, Jesús-Kim LD, Hernández-Rivera S, Zagorevski DV, López-Garriga J, Lednev IK.
Journal: J Phys Chem B. 2015 Jan 29;119(4):1265-74.
PMID: 25545790 (This article is OPEN ACCESS if you would like to read it)
Amyloid formations are large clusters of misfolded proteins that are associated with neurodegenerative conditions, like Alzheimer’s disease and Parkinson’s disease. The researchers who conducted this study were interested in the behaviour of these misfolded protein in the presence of hydrogen sulfide. What they found was rather remarkable: the addition of hydrogen sulfide completely inhibited the formation amyloid fibrils (amyloid fibril plaques are found in brains of people with Alzheimer’s disease).
If the addition of hydrogen sulfide can reduce the level of clustered proteins in a model of Alzheimer’s disease, it would be interesting to see what it would do to alpha synuclein.
NOTE: Hydrogen sulfide levels are also reduced in the brains of people with Alzheimer’s disease (click here to read more on this topic)
Has hydrogen sulfide ever been tested in the clinic?
There are currently 17 clinical trials investigating hydrogen sulfide in various conditions (not Parkinson’s disease though).
So where can I get me some of that hydrogen sulfide?
Ok, so here is where we come in with the health warning section.
You see, hydrogen sulfide is a very dangerous gas. It is really not to be played with.
The gas is both corrosive and flammable. More importantly, at high concentrations, hydrogen sulfide gas can be fatal almost immediately (>1000 parts per milllion – source: OSHA). And the gas only exhibits the “rotten eggs” smell at low concentrations. At higher concentrations it becomes undetectable due to olfactory paralysis (luckily for the folks in Rotorua, the levels of hydrogen sulfide gas there are between 20-25 parts per billion).
Thus, we do not recommend readers to rush out and load up on hydrogen sulfide gas.
There are many foods that contain hydrogen sulfide.
For example, garlic is very rich in hydrogen sulfide. Another rich source is cooked beef, which has about 0.6mg of hydrogen sulfide per pound – cooked lamb has closer to 0.9 milligrams per pound. Heated dairy products, such as skim milk, can have approximately 3 milligrams of hydrogen sulfide per gallon, and cream has slightly more than double that amount.
Any significant change in diet by a person with Parkinson’s disease should firstly be discussed with a trained medical physician as we can not be sure what impact such a change would have on individualised treatment regimes.
What does it all mean?
Summing up: It would be interesting to look at the frequency of Parkinson’s disease in geothermal region of the world (the population of Rotorua is too small for such an analysis – 80,000 people).
Researchers believe that components of the gas emissions from these geothermal areas may be neuroprotective. Of particular interest is the gas hydrogen sulfide. At high levels, it is a very dangerous gas. At lower levels, however, researchers have shown that hydrogen sulfide has many beneficial properties, including in models of neurodegenerative conditions. These findings have led many to propose testing hydrogen sulfide in clinical trials for conditions like Parkinson’s disease.
Dr Cakmak, who we mentioned near the top of this post, goes one step further. He hypothesises that hydrogen sulfide may actually be one of the active components in the neuroprotective affect of both coffee and smoking – and with good reason. It was recently demonstrated that the certain gut bacteria, such as Prevotella, are decreased in people with Parkinson’s disease (see our post on this topic by clicking here). The consumption of coffee has been shown to help improve the Prevotella population in the gut, which may in term increase the levels of Prevotella-derived hydrogen sulfide. Similarly smokers have a decreased risk of developing Parkinson’s disease and hydrogen sulfide is a component of cigarette smoke.
All of these ideas still needs to be further tested, but we are curious to see where this research could lead. An inhaled neuroprotective treatment for Parkinson’s disease may have benefits for other neurodegenerative conditions.
Oh, and if anyone is interested, we are happy to put readers in contact with real estate agents in sunny ‘Rotten-rua’, New Zealand. The locals say that you gradually get used to the smell.
EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs/molecules discussed on this website are clinically available, they may have serious side effects. We therefore urge caution and professional consultation before any attempt to alter a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.
The banner for today’s post was sourced from Trover
I really didn’t expect to be writing about Parkinson’s research being conducted in New Zealand again so quickly, but yesterday a new study was published which has a few people excited.
It presents evidence of how the disease may be spreading… using cells collected from people with Parkinson’s disease.
In today’s post we will review the study and discuss what it means for Parkinson’s disease.
The South Island of NZ from orbit. Source: Sciencenews
We may have mentioned the protein Alpha synuclein once or twice on this blog.
For anyone familiar with the biology of Parkinson’s disease, alpha synuclein is a major player. It is either public enermy no.1 in the underlying pathology of this condition or else it is the ultimate ‘fall guy’, left standing in the crime scene holding the bloody knife.
Remind me, what is alpha synuclein?
Alpha synuclein is an extremely abundant protein in our brains – making up about 1% of all the proteins floating around in each neuron (one of the main types of cell in the brain).
In healthy brain cells, normal alpha synuclein is typically found just inside the surface of the membrane surrounding the cell body and in the tips of the branches extending from the cell (in structures called presynaptic terminals which are critical to passing messages between neurons).
And why is alpha synuclein important in Parkinson’s disease?
Genetic mutations account for 10-20% of the cases in Parkinson’s disease.
Five mutations in the alpha-synuclein gene have been identified which are associated with increased risk of Parkinson’s disease (A53T, A30P, E46K, H50Q, and G51D – these are coordinates for locations on the alpha synuclein gene). Rare duplication or triplication of the gene have also been associated with Parkinson’s disease.
The structure of alpha synuclein protein – blue squares are mutations. Source: Mdpi
So genetically, alpha synuclein is associated with Parkinson’s disease. But it is also involved at the protein level.
In brains of many people with Parkinson’s disease, there are circular clumps of alpha synuclein (and other proteins) that collect inside cells. These clumps are called Lewy bodies. They are particularly abundant in areas of the brain that have suffered cell loss.
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
No one has ever seen the process of Lewy body formation, so all we can do is speculate about how these aggregates develop. Currently there is a lot of evidence supporting the idea that alpha synuclein can be passed between cells. Once inside the new cell, the alpha synuclein helps to seed the formation of new Lewy bodies, and this is how the disease is believed to progress.
Exactly how alpha synuclein is being passed between cells is the topic of much research at the moment. There are many theories and some results implicating methods such as direct penetration, or via a particular receptor. Perhaps even by a small package called an exosome being passed between cells (see image above).
How this occurs in the Parkinson’s disease brain, however, is unknown.
And this (almost) brings us to the kiwi scientists.
Last years, a group of Swiss scientists demonstrated that alpha synuclein could be passed between cells via ‘nanotubes’ – tiny tubes connecting between cells. The outlined their observations and results in this article:
Title: Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes.
Authors: Abounit S, Bousset L, Loria F, Zhu S, de Chaumont F, Pieri L, Olivo-Marin JC, Melki R, Zurzolo C.
Journal: EMBO J. 2016 Oct 4;35(19):2120-2138.
The researchers who conducted this study were interested in tunneling nanotubes.
Yes, I know, ‘What are tunneling nanotubes?’
Tunneling nanotubes (also known as Membrane nanotubes or cytoneme are long protrusions extending from one cell membrane to another, allowing the two cells to share their contents. They can extend for long distances, sometimes over 100 μm – 0.1mm, but that’s a long way in the world of cells!
Previous studies had demonstrated that tunneling nanotubes can pass different infectious agents (HIV for example – click here to read more on this), supporting the idea that these structures could be a general conduit by certain diseases could be spreading.
A tunneling nanotube between two cells. Source: Pasteur
In their study the Swiss researchers found that alpha synuclein could be transferred between brain cells (grown in culture) via tunneling nanotubes. In addition, following that process of transfer, the alpha synuclein was able to induce the aggregation (or clumping) of the alpha synuclein in recipient cells.
A particularly interesting finding was that alpha synuclein appeared to encourage the appearance of tunneling nanotubes (there were more tunneling nanotubes apparent when cells produced more alpha synuclein). And the alpha synuclein that was being transferred was being passed on in ‘lysosomal vesicles’ – these are the rubbish bags of the cell (lysosomal vesicles are used to take proteins away for degradation).
Paints a rather insidious picture of the ‘ultimate fall guy’ huh!
And that image was made worse by the results published by the kiwis last night:
Title: α-synuclein transfer through tunneling nanotubes occurs in SH-SY5Y cells and primary brain pericytes from Parkinson’s disease patients
Authors: Dieriks BV, Park TI, Fourie C, Faull RL, Dragunow M, Curtis MA.
Journal: Scientific Reports, 7, Article number: 42984
PMID: 28230073 (This article is OPEN ACCESS if you would like to read it)
In their study, the New Zealand scientists extended the Swiss research by looking at cells collected from people with Parkinson’s disease. The researchers took human brain pericytes, which were derived from the postmortem brains of people who died with Parkinson’s disease.
And before you ask: pericytes are cells that wrap around the cells lining small blood vessels. They are important to the development of new blood vessels and maintaining the structural integrity of microvasculature.
A pericyte (blue) hugging a blood vessel (red). Source: Xvivo
Pericytes contain alpha synuclein precipitates like those seen in neurons, and the kiwi scientists demonstrated that pericytes too can transfer alpha synuclein via tunneling nanotubes to neighbouring cells – representing a non-neuronal method of transport.
They also found that the transfer through the tunneling nanotubes can be very rapid – within 30 seconds – and the transferred alpha synuclein can hang around for more than 72 hours, suggesting that it is difficult for the receiving cell to dispose of. The researchers did note that the transfer through tunneling nanotubes occurred only in small subset of cells, but that this could explain the slow progression of Parkinson’s disease over time.
What does it all mean?
In order for us to truly tackle Parkinson’s disease and bring it under control, we need to know how this slowly progressing neurodegenerative condition is spreading. Some researchers in New Zealand have provided evidence involving cells collected from people with Parkinson’s disease that indicates one method by which the disease could be passed from one cell to another.
Tiny tunnels between cells, allowing material to be shared, could explain how the disease slowly progresses. The scientists observed the Parkinson’s associated protein alpha synuclein being passed between cells and then hanging around for more than a few days.
This method of transfer was made more interesting because the New Zealand researchers reported that non-neuronal cells (Pericytes, collected from people with Parkinson’s disease) could also form tunneling nanotubes. This observation raises questions as to what role non-neuronal cells could be playing in Parkinson’s disease.
This line of questions will obviously be followed up in future research, as will efforts to determine if tunneling nanotubes are actually present in the human brain or simply biological oddities present only in the culture dish. Demonstrating nanotubes in the brain will be difficult, but it would provide us with solid evidence that this method of disease transfer could be a bonafide cause of disease spread.
We watch with interest for further work in this area.
FULL DISCLOSURE: The author of this blog is a kiwi… and proud of it. He is familiar with the researchers who have conducted this research, but has had no communication with them regarding the publishing of this post. He simply thought that the results of their study would be of interest to the Parkinson’s community.
The banner for today’s post was sourced from Pinterest
This is one of the first immuno-therapies being tested in Parkinson’s disease, and the results indicate that the treatment was active and well tolerated.
In this post we will review the press release and what it tells us regarding this clinical trial.
Antibodies binding to proteins. Source: AXS
When your body is infected by a foreign agent, it begins to produce some things called antibodies. In most cases, these are Y-shaped proteins that binds to the un-wanted invader and act as a beacon for the immune system. It is a very effective system, allowing us to go about our daily business without getting sick on a regular basis. Antibodies allow us to build up immunity, or resistance of an organism to infection or disease.
Scientist have harnessed the power of this natural process, and they have use it to develop methods of helping our bodies fight off disease.
The first approach is called Acquired Immunity (or adaptive immunity), and it is based on the idea that exposure of the immune system to a pathogen (disease/damage causing agent) creates an ‘immunological memory’ within our immune system, and this leads to an enhanced response to subsequent future encounters with that same pathogen.
Scientists have used the idea of acquired immunity to develop what we call vaccines – which are simply small, neutral fragments of specific pathogen that help the immune system to build up immunity (or resistance) before the body is attacked by the disease-causing pathogen itself.
Vaccination. Source: WebMD
The second approach is called Passive Immunity.
Passive immunisation is simply the sharing of antibodies. And that might sound a bit disturbing, but it is actually a naturally occurring process. For example, a mother’s antibodies are transferred to her baby in the womb via the placenta.
And again, scientists have devised ways of producing passive immunisation artificially. And recently researchers have been using this approach to attack many medical conditions (particularly cancer), in an area of medicine called immunotherapy.
Think of it as simply boosting the immune system by supplementing the supply of antibodies. Scientists can produce high levels of antibodies that specifically target a particular pathogen and then transfer those antibodies to affected people via an intravenous injection.
How is this being used for Parkinson’s disease?
Well, we have previously discussed the idea of a vaccine for Parkinson’s disease (click here to read that post), and we have been closely following the progress of an Austrian company, AffiRis, who are leading the vaccination approach (Click here for that post).
The vaccine approach is targeting the Parkinson’s disease associated protein, Alpha synuclein. It is believed that a bad kind of alpha synuclein is causing the spread of the condition, by being passed from cell to cell. The goal of the vaccine is to capture and remove all of the alpha synuclein being passed between cells and thus (hopefully) halt the progress of – or at least slow down – the disease.
And this week, another company – Prothena – has reported the results of their phase 1 trial for a passive immunity approach to Parkinson’s disease. They have been injecting subjects in the trial with a treatment called PRX002.
(Remember that a phase 1 trial simply tests the safety of a treatment in humans, it is not required to test efficacy of the treatment. Efficacy comes with phases 2 & 3 trials)
What is PRX002?
PRX002 is a monoclonal antibody. The scientists at the biotech company Prothena have artificially produced large amounts of antibodies to alpha synuclein and these have been injected into people with Parkinson’s disease.
Monoclonal antibodies. Source: Astrazeneca
Prothena provide a short video explaining this concept (click here to view the video).
So what were the results of the Prothena study?
The study was conducted in collaboration the pharmaceutical company Roche. It was a double-blind (so both the researchers and subjects did not know what they were receiving until the conclusion of the study), placebo-controlled study involving 80 people with Parkinson’s disease. The subjects were randomly assigned to one of six groups, which received either PRX002 or a placebo. There were six doses of PRX002 tested in the study (0.3, 1, 3, 10, 30 or 60 mg/kg).
The study was conducted over six-month, during which patients received three once-a-month injections of either PRX002 or placebo. The subjects were then followed for an observational period of three months.
According to the press release, no serious treatment-related adverse events were reported in PRX002 treated patients. Mild treatment-related adverse events (greater than anything experienced within the placebo group) were noted in 4 of the 12 subjects in the highest dosage group of PRX002, including constipation and diarrhoea.
Importantly, the investigators reported that thePRX002 antibodies were crossing the blood brain barrier and entering the brain. This resulted in a rapid reduction of alpha-synuclein levels (in some cases by up to 97 percent after a single dose!).
The follow-on Phase 2 clinical study is expected to begin in 2017.
What is the difference between the vaccine and the passive immunity approaches?
Basically, it comes down to levels of control. With a vaccination, once you have injected the vaccine and the immune system is activated, there isn’t much you can do to control the response of the body. And that immune memory is going to last a long time. The passive immunity response, on the other hand, requires regular injections of antibodies which can be stopped if adverse effects are noted.
Plus – and forgive me if I sound a little bit cynical here – drug companies prefer a regular treatment approach (which they can charge for each visit) compared to a one-shot cure. It’s simply a better business model.
What happens next?
In both cases – the vaccine and the passive immunity approaches – phase 2 trials are being set up by the respective companies and we will wait to see have affective these treatments are at slowing down Parkinson’s disease.
If they are affective, expect big headlines in the media and plans for adults everywhere to start being vaccinated. If they fail,…. well, we will have to re-address our understanding of the role of alpha synuclein in Parkinson’s disease.
Interesting times lie ahead.
The banner for todays post was sourced from Prothena
In 2000, a research paper investigating the incidence of Parkinson’s disease in Bulgaria was published in the journal Neuroepidemiology.
The results were rather startling.
In their study, the researchers included a subpopulation of over 6,000 gypsies. In a population of that size they had expected to find 10-30 cases of Parkinson’s disease (based on the incidence in other populations of people).
What they actually found didn’t make any sense.
In this post we will look at the incidence of Parkinson’s disease around the world and why the Bulgarian gypsies are unique in the data.
Bulgarian gypsies. Source: Youtube
Trying to determine how frequently a particular phenomenon occurs within a given population sounds like a pretty straightforward task, right?
In practise, however, it proves to be very difficult. In some cases, almost impossible. In the western/developed world – where the medical records databases exist – the task of determining certain medical characteristics within a population of interest is slightly easier, but most experts will agree that most measures of incidence still include a pinch of error and a smidgen of guesstimating.
Beyond the developed world, determining incidence in a population is a ‘door-knocking’ job. Researchers literally have to go from house to house and asking for a survey to be filled in, or conduct doorstep evaluations of the inhabitants. A much harder task and cultural characteristics begin to play a role in the outcomes (such as lower incidence of a particular disease in communities that don’t like to ‘lose face’).
Additional problems with measuring incidence
Other problems with measuring incidence within a population include:
- Unimpeded access to the population (eg. some people live in isolated locations/communities)
- Accurate measures/criteria of the disease (eg. remember we don’t have an accurate diagnostic test for Parkinson’s disease)
- No response bias (posted surveys receive a limited response, and many affected individuals within a community will live with a condition without alerting their doctor)
- The size of the effect (if only one or two people are affected by a characteristic, the task of determining incidence becomes much harder – consider the very low incidence of juvenile onset Parkinson’s disease – Click here for more on this)
With all of that said, many efforts have been made in trying to determine the incidence of Parkinson’s disease. Some consensus has become apparent, but there are some interesting differences.
The incidence of Parkinson’s disease
The incidence of Parkinson’s disease varies around the world and there are some interesting differences.
Most studies agree, however, that the incidence of Parkinson’s disease is approximately 0.3% of the general population in industrialized countries. That is, 1 person in every 2-300. As we are all aware, Parkinson’s disease is more common in the elderly, and as such the incidence rises to about 1% (or 1 in 100) in those over 60 years of age. The incidence rate continues to rise with age to 4% of the population over 80 years of age (almost 1 in every 20 people over 80 year of age).
In 2009, Parkinson’s UK published their report on the incidence of Parkinson’s disease within the UK and their numbers are very similar to those summarised above (Click here for a PDF file of that report).
Disease burden – another way of measuring a disease
Many epidemiologists (the people who measure all of this incidence stuff) now incorporate a different kind of population-disease measurement into their analysis: ‘Disease burden’.
Below is a map of ‘hotspot’ countries (in red) around the world that have the disease burden due to Parkinson’s disease according to the World Health Organisation (WHO) (click here for their raw data – Microsoft Excel file).
A world map of Parkinson’s disease burden (red = high incidence). Source: Wikipedia
The map illustrates the disability-adjusted life year (DALY) rates from Parkinson disease by country (per 100,000 inhabitants).
Yeah I know. It sound complicated, but it isn’t really.
The DALY is simply a measure of the overall disease burden that a population experiences, and it is expressed as the number of years lost due to ill-health, disability or early death. Put another way, the DALY for any given country is calculated by taking the total number of the years of life lost due to dying early and adding it to the number of years lost due to disability. So for the map above, the Maldives (dark red dot in the Indian Ocean) exhibits the highest burden with the country loses 557 years per 100,000 inhabitants.
And importantly these measures are ‘age adjusted’, so that countries with a higher proportion of elderly people (such as Japan) do not appear to have a higher burden due to Parkinson’s disease than a country with a younger population. The WHO numbers are provided by the government health services in each country.
The highest incidence of Parkinson’s disease
Ok, so if we leave the global/macro world of Parkinson’s disease incidence and focus on particular nations/communities of people, what does the research literature tell us about the incidence of Parkinson’s disease?
Well, one of the highest incidence occurs in the Amish community of the US midwest.
The Amish communities of the American midwest. Source: DartMed
The Amish community started in Switzerland in the 17th century. In the 18th and 19th centuries, many adherents
immigrated to the USA in an attempt to flee religious persecution. They now live in communities rather culturally isolated from society – maintaining a traditional way of life, ignoring the modern conveniences, and
marrying strictly within their religion (maintaining strict endogamy). They are not completely isolated, however, as they are work/conduct business with mainstream society. From a scientific standpoint, the Amish are a wonderful cases study. They have diligently kept meticulous family records dating far back in history. In addition, they forbid consumption of alcohol or use of tobacco.
Many years ago, researchers began to notice a high incidence of Parkinson’s features within the community. Several population studies have been conducted on the Amish, including this one:
Title: A population-based study of parkinsonism in an Amish community.
Authors: Racette BA, Good LM, Kissel AM, Criswell SR, Perlmutter JS.
Journal: Neuroepidemiology. 2009;33(3):225-30.
PMID: 19641327 (This article is OPEN ACCESS if you would like to read it)
The researcher in this study tried to recruit all of the individuals over the age of 60 (total 262 people) in an Old-Order Amish community of 4,369 people. Of the 213 subjects who agreed to participate, 15 had Parkinson’s disease while a further 73 individuals had a UPDRS (Unified Parkinson’s Disease Rating Scale) motor score of >9 (indicating early stages of Parkinson’s). The researchers calculated the prevalence of Parkinson’s disease in this population of people at 5,703/100,000 or 5% of the population over 60 years of age. This was far higher than the 1% of the 60+ years population in the rest of the world.
There are over 200,000 Amish in North America, and they have played a prominent historical role in Parkinson’s disease research – the first Parkinson’s-related genetic mutations were identified in genetically isolated Amish populations (Click here for more on this). The genetics of Parkinson’s disease in the Amish is not clear, however, as a recent large population analysis demonstrated:
Title: Parkinson disease loci in the mid-western Amish.
Authors: Davis MF, Cummings AC, D’Aoust LN, Jiang L, Velez Edwards DR, Laux R, Reinhart-Mercer L, Fuzzell D, Scott WK, Pericak-Vance MA, Lee SL, Haines JL.
Journal: Hum Genet. 2013 Nov;132(11):1213-21.
PMID: 23793441 (This article is OPEN ACCESS if you would like to read it)
The scientists behind this study collected DNA samples from 798 individuals (31 with diagnosed Parkinson’s disease) who are part of a 4,998 individuals living in the Amish communities of Indiana and Ohio. Although there were a couple of areas of DNA that may confer susceptibility towards Parkinson’s disease, the researchers did not find any major/significant regions (or loci) suggesting that even within the Amish the genetics of Parkinson’s disease may be more extensive than previously appreciated.
Is there a gender bias in the incidence of Parkinson’s disease?
Yes there is.
On average women have a later onset of Parkinson’s disease than men. In addition, around the world, men are more likely to be affected by Parkinson’s disease than women by a ratio of approximately 2:1.
Curiously, there is one country that bucks this trend: Japan
There are now several studies that find the incidence of Parkinson’s disease in Japan is higher in females than males (Click here for more on this), and we have previously looked at this curious difference in a previous post (Click here to read that post)
Is there any evidence that the incidence of Parkinson’s disease is increasing?
Interesting question, and yes there is:
Title: Time Trends in the Incidence of Parkinson Disease
Authors: Savica R, Grossardt BR, Bower JH, Ahlskog JE, Rocca WA.
Journal: JAMA Neurol. 2016 Aug 1;73(8):981-9.
This very recent study analysed the incidence of Parkinson’s disease by using medical records from the Rochester Epidemiology Project to identify incidence cases of Parkinson’s disease and other types of parkinsonism in Olmsted County (Minnesota) between 1976 to 2005. And the researchers made an interesting discovery: between 1976 and 2005, the incidence of Parkinson’s disease has increased, particularly in men 70 years and older. The researchers speculate as to whether this increase is associated with a dramatic decrease in the rates of smoking or other environmental/life styles changes.
We should add that there is some research that refutes this finding and we are waiting to see what follow up analysis shows us – we will report that when it is available.
So what about the Bulgarian gypsies?
Oh yeah, almost forgot.
Title: Prevalence of Parkinson’s disease in Bulgarian Gypsies.
Authors: Milanov I, Kmetski TS, Lyons KE, Koller WC.
Journal: Neuroepidemiology. 2000 Jul-Aug;19(4):206-9.
So between January and November of 1997, the Bulgarian scientists sent out their questionnaire, and they conducted door-to-door visits, eventually collecting a pool of over 6,000 people of gypsy descent. They were trying to determine the incidence of Parkinson’s disease within this community, but what they discovered was not what they expected:
Just one case of Parkinson’s disease.
A 61 year old man.
Given the incidence in most other communities, in a population of 6,000 people one might expect to see maybe 20 cases. Not just one!
The researchers concluded that the prevalence of Parkinson’s disease in the Gypsies was found to be 16/100,000 (based on that 1 case out of 6163 people), compared to 137/100,000 for Caucasians (based on 119 cases from 87,025 people). This means that Bulgarian gypsies have the lowest incidence of Parkinson’s disease in the world.
Our answer: ????
We really do not know. No one does.
The authors of the research paper suggest that gypsies are believed to originate from North India, and given that the inhabitants of Asia have a lower rate of Parkinson’s disease than their western counterparts, this may partly explain the low frequency in the Bulgarian gypsies. This is only applicable, however, if similar low rates of Parkinson’s disease are found in other gypsy populations. To our knowledge, these studies have not been done (please feel free to correct us on this matter).
The banner for today’s post was sourced from BalkanMusicNight