In today’s post we are going to look at a recent piece of research that suggests some of the bacteria in our gut can influence the availability of the medication we use to treat Parkinson’s.
In addition, we will look at a novel way researchers are re-engineering bacteria in the gut to correct other medical conditions (such as phenylketonuria) and we will ask if the same can not be applied to Parkinson’s.
The Platypus. Source: National geographic
The interesting, but utterly useless fact of the day: The duck-billed Platypus of Australia does not have a stomach.
No really. These oddities of evolution have no stomach. There’s no sac in the middle of their bodies that secrete powerful acids and digestive enzymes. The oesophagus (the tube from the mouth) of the platypus connects directly to its intestines.
The platypus. Source: Topimage
And believe it or not, platypus are not alone on this ‘sans estomac‘ trend. At least a 1/4 of the fish species on this planet do not have a stomach (Source).
And this absense of the stomach isn’t even remotely weird in the animal kingdom. Some creatures don’t even have a gastrointestinal system. No mouth. No anus. No intestines. Nothing.
The giant tube worm – Riftia pachyptila – lives on the floor of the Pacific Ocean, next to hot hydrothermal vents and can tolerate extremely high levels of hydrogen sulfide (hazardous for you and I). These creatures – which can grow up to 2.4 meters (or 7+ feet) in length – have no gastrointestinal tract whatsoever. Zip, zero, nada.
Rather they have an internal cavity – called a trophosome – filled with bacteria which live symbiotically with them.
Watch this video of Ed Yong explaining it all (great video!):
WOW! Fascinating! But what does ANY of this have to do with Parkinson’s?
An important aspect of developing better remedies for Parkinson’s involves determining when and where the condition starts in the brain. What is the underlying mechanism that kicks things off and can it be therapeutically targetted?
Recently, researchers from Japan have suggested that a protein called Myristoylated alanine-rich C-kinase substrate (or simply MARCKS) may be a potentially important player in the very early stages of Parkinson’s (and other neurodegenerative conditions).
Specifically, they have found that MARCKS is present before many of the other pathological hallmarks of Parkinson’s (such as Lewy bodies) even appear. But what does this mean? And what can we do with this information?
In today’s post, we will look at what MARCKS is, what new research suggests, and how the research community are attempting to target this protein.
Where does it all begin? Source: Cafi
One of the most interesting people I met during my time doing Parkinson’s assessment clinics was an ex-fire forensic investigator.
We would generally start each PD assessment session with a “brief history” of life and employment – it is a nice ice breaker to the appointment, helped to relax the individual by focusing on a familiar topic, and it could provide an indication of potential issues to consider in the context of Parkinson’s – such as job related stress or exposure to other potential risk factors (eg. pesticides, etc).
But so fascinated was I with the past emplyoment of the ex-fire forensic investigator gentleman that the “brief history” was anything but brief.
We had a long conversation.
One aspect of fire forensics that particularly fascinated me was the way he could walk into a recently burned down property, and he could “read the story backwards” to identify the root cause of the fire.
He could start anywhere on a burnt out property and find his way back to the source (and also determine if the fire was accidental or deliberate).
Where did it all start? Source: Morestina
I marvelled at this idea.
And I can remember wondering “why can’t we do that with Parkinson’s?”
Well, recently some Japanese researchers have had a crack at “reading the story backwards” and they found something rather interesting.
What did they find?
Lipids are ‘waxy’ molecules that make up a large proportion of your brain and they play very important roles in normal brain function. For a long time researchers have also been building evidence that lipids may be involved with neurodegenerative conditions as well.
Recently, new research was presented that supports this idea (in the case of Parkinson’s at least), as two research groups published data indicating that certain lipids can influence the toxicity of the Parkinson’s associated protein alpha synuclein.
One of those research groups was a biotech company called Yumanity, and they are developing drugs that target the enzymes involved with the production of the offending lipids.
In today’s post, we will look at what lipids are, what the new research suggests, and discuss some of the issues that will need to be considered in the clinical development of these lipid enzyme inhibitors.
Yummy. Source: Healthline
There has been the suggestion from some corners that this association may be due to the richness of monounsaturated fats in the foods generally included in this diet.
For example, olive oil is rich in monounsaturated fat.
What are monounsaturated fats?
Mmmm, before I answer that we need to have a broader discussion about “what is fat?“.
Fat is one of the three main macronutrients (carbohydrate and protein being the other two) that the body requires for survival.
Fat serves as a ready source of energy for the body and can also provide insulation against cold temperatures or compression. All fats are derived from combinations of fatty acids (and also glycerol).
What are fatty acids?
A fatty acid is simply a chain of hydrocarbons terminating in a carboxyl group (having a carbonyl and hydroxyl group both linked to a carbon atom). Don’t worry too much about what that means, just understand that fatty acids are basically chains of hydrocarbons that look like this:
A chain of hydrocarbons ending in a carboxyl group (right). Source: Wikipedia
Fatty acids come in two forms:
In the case of a saturated fat, each carbon molecule in the chain of hydrocarbons is bonded to two other carbons by a single bond. Whereas in the case of a saturated fat, one or more carbon molecule in the chain of hydrocarbons is bonded to another carbon molecule by a double bond. For example:
Saturated fatty acids vs unsaturated fatty acids. Source: Medium
And unsaturated fatty acids can be further divided into:
- Monounsaturated fatty acids (or MUFAs) are simply fatty acids that have a single double bond in the fatty acid chain with all of the remainder carbon atoms being single-bonded.
- Polyunsaturated fatty acids (or PUFAs) are fatty acids that have more than one double bond.
OK, but how might monounsaturated fats be involved with Parkinson’s?
That, dear reader, is the focus of numerous studies in the field of lipidomics.
What is lipidomics?
Recently I wrote a post about research investigating an interesting compound called Epigallocatechin gallate (or EGCG – click here for that post). Several eagle-eyed readers, however, noted something interesting in the details of one of the research reports that was discussed in that post.
The study in question had used EGCG as a positive control for evaluating the ability of other compounds for their ability to inhibit the clustering of Parkinson’s-associated protein alpha synuclein.
But there was also a second positive control used in that study.
It is called baicalein.
In today’s post, we will discuss what baicalein is and what research has been done on it in the context of Parkinson’s.
Lake Baikal. Source: Audleytravel
Once upon a thyme, in a far away land, there was a mysterious little flowering plant.
The “far away land” was the southern parts of eastern Siberia.
And the flowering plant is Scutellaria baicalensis – which is more commonly referred to as Baikal skullcap.
What is Baikal skullcap?
Baikal skullcap is a perennial herb that is indigenous to Southern Siberia, China and Korea. For centuries, traditional Chinese medicine has used the dried roots – which is called huángqín (Chinese: 黄芩 or golden root) – for a variety of ailments.
Baikal skullcap. Source: Urbol
The plant grows to between 1-4 feet in height, with lance head-shaped leaves and blue-purple flowers. Baikal skullcap belongs to the same family of flowering plants (Lamiaceae) as thyme, basil, mint and rosemary.
For traditional Chinese medicinal use, the roots are usually collected in spring or autumn once the plant is more than 3-4 years old. They are dried and then used to treat hypertension, to reduce “fire and dampness”, and to treat prostate & breast cancers.
And one of the key constituents of Baikal skullcap (and huángqín) is a compound called baicalein.
What is baicalein?
A new research report has been published this week which may point not only towards a new understanding of the biology of Parkinson’s, but also to potentially novel therapies which are clinically available.
These exciting new findings involve a DNA repair mechanism called ‘poly ADP ribose polymerase’ (or simply PARP) and a process of cell death called Parthanatos.
Biotech companies have developed PARP inhibitors which have been reported to rescue models of Parkinson’s. With a bit of tweaking, this class of drugs could potentially be re-purposed for Parkinson’s.
In today’s post, we will look at what PARP is, explain how PARP inhibitors work, review what previous PD research has been conducted on this topic, evaluate the new report, and consider what it means for the Parkinson’s community (Spoiler alert: this will be a long post!).
Ah, the good old days!
Remember them. Way back before Netflix. When life was sooo much easier.
You know what I’m talking about.
Back when biology was simple. Remember when DNA gave rise to RNA and RNA gave rise to protein, and that was it. Simpler times they were. Now, everything is so much more complicated. We have all manner of ‘regulatory RNA’, epigentics, splice variants, and let’s not get started on the labyrinthian world of protein folding.
Oh, how I long for the good old days.
Back when a cell could only die one of two ways: apoptosis (a carefully controlled programmed manner of death) and necrosis (cell death by injury):
Now life is too complicated and complex beyond reason or imagination.
Let’s just take the example of cell death that I mentioned above: over the past decade, the Nomenclature Committee on Cell Death (or NCCD – I kid you not there is actually a committee for this) has written up guidelines for the definition/interpretation of ‘cell death’. And as part of that effort they have decided that there are now at least 12 (yes, 12) different ways a cell can die:
For those of who are interested in reading more about all of these different kinds of cell death, click here to read NCCD committee’s most recent recommendations which were updated this year (2018). Some riveting betime reading.
Which form of cell death applies to Parkinson’s?
Now that’s a really good question!
One that has been studied and the source of debate for a very long time.
To be fair, we don’t really know. But fascinating new research published this week suggests that the Parthanatos pathway could be involved in the cell death associated with Parkinson’s.
What is Parthanatos?
Many novel therapies are currently being clinically tested in Parkinson’s, and this week we heard the results of one clinical trial which provided some very interesting news.
Intra-Cellular Therapies has been testing their drug, ITI-214 – which is a potent and selective phosphodiesterase 1 (PDE1) inhibitor. Inhibitors of PDE1 prevent the breakdown of protein called cyclic nucleotides (cAMP, cGMP).
The results of the Intra-Cellular Therapies clinical trial suggest that in people with Parkinson’s, the drug not only improves symptoms, but also reduces dyskinesias.
In today’s post we will discuss what PDE1 is, how PDE1 inhibitors work, and what the results of the clinical trial suggest.
Every year in October, the American Neurology Association (ANA) gather in one of the major US cities to share research regarding neurological condtions, like Parkinson’s. And while I did not attend the ANA meeting this year, I was keen to hear the results of one particular clinical study.
It was a trial conducted by a company called Intra-Cellular Therapies.
What is special about ITI-214?
ITI-214 is a Phosphodiesterase inhibitor.
What is a phosphodiesterase inhibitor?
Lewy bodies are densely packed, circular clusters of protein that have traditionally been considered a characteristic feature of the Parkinsonian brain. Recently, however, evidence has been accumulating which calls into question this ‘defining feature’ of the condition.
The presence Lewy bodies in some cases of other neurological conditions (such as Alzheimer’s), and their complete absence in some cases of Parkinson’s, are leading many researchers to question their pivotal role in PD.
In today’s post, we will look at a new research report of Parkinson’s post mortem cases studies which present no Lewy bodies, and we will disucss what this might mean for our understanding of Parkinson’s and the future treatment of the condition.
Neuropathologists conducting a gross examination of a brain. Source: NBC
At present, a definitive diagnosis of Parkinson’s can only be made at the postmortem stage with an examination of the brain. Until that moment, all cases of Parkinson’s 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). As the name suggests, the substantia nigra region is visible due to the production of a ‘substance dark’ molecule called neuromelanin in the dopamine neurons. And as you can see in the image below, the Parkinsonian brain has less dark pigmented cells in the substantia nigra region of the midbrain.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinsonian 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
A Lewy body is referred to as a cellular inclusion, 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) and 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
Do all Parkinson’s brains have Lewy bodies?
This is a really interesting question. Welcome to the topic of this post.
Alpha synuclein is a protein that is closely associated with Parkinson’s. But exactly if and how it is connected to the neurodegenerative process underlying the condition, remains unclear.
Last week researchers reported that removing a particular form of alpha synuclein in mice results in a very early onset appearance of characteristics that closely resemble the features of Parkinson’s that we observe in humans. This finding has caused some excitement in the research community, as not only does this tell us more about the alpha synuclein protein, but it may also provide us with a useful, more disease-relevant mouse model for testing therapies.
In today’s post, we will discuss what alpha synuclein is, explain which form of the protein was disrupted in this mouse model, review the results of the new study, and look at how tetramer stablising drugs could be a new area of PD therapeutics.
The 337 metre (1,106 ft) long USS Gerald R. Ford. Source: Wikipedia
Imagine you and I are standing in front of the world’s largest aircraft carrier, the USS Gerald R. Ford.
It is a VAST warship – measuring in at 337 metres (1,106 ft) in length, 76 metres (250 feet) in height – and it is a wonder of engineering composed of over a billion individual components.
And as we are standing there, gazing up at this amazing machine, I turn to you and put a nut & bolt into the palm of your hand.
A nut and bolt. Source: Atechleader
You look down at it for a moment, then turn to me, puzzled.
And that is when I say: “I would like you to find (without aid/instructions) where on this ship versions of this particular type of nut and bolt live, and try to determine exactly what functions they have“.
Where would you even start?
What tools would you use for the job? Considering the size and complexity of the vessel, would you simply give up before even starting?
It sounds like a ridiculously daunting task, but this is in effect what neurobiologists are trying to do with their study of the brain. They start with a protein – one of the functional pieces of machinery inside each cell of our body – and then try to determine where in the brain it lives (the easy part) and what it does exactly (the REALLY hard part – most proteins have multiple functions and different configurations).
A good example of this is the Parkinson’s-associated protein alpha synuclein:
Alpha synuclein. Source: Wikipedia
Alpha synuclein is one of the most abundant proteins in our brains – making up about 1% of all the proteins floating around in each neuron in your head – and it is a very well studied protein (with over 9700 research reports listed on the Pubmed search engine with the key words ‘alpha synuclein’).
But here’s the thing: we are not entirely clear on what alpha synuclein actually does inside the cell.
In fact, biologists are not even sure about what the ‘native’ form of alpha synuclein is!
What do you mean?
The clustering (or aggregation) of the protein, alpha synuclein, is a cardinal feature of the Parkinsonian brain, and it is believed to be associated with the neurodegeneration that characterises the condition.
As a result, many pharmaceutical and biotech companies are focused a great deal of attention on identifying novel compounds that can enter the brain and inhibit alpha synuclein from aggregating. Recently, a collaboration of companies published the results of an amazingly large study highlighting novel inhibitors.
But an interesting aspect of the results was the ‘positive control’ compound they used: Epigallocatechin Gallate (or simply EGCG)
In today’s post, we will review the results of the study, discuss what EGCG is, and look at what is known about this compound in the context of Parkinson’s.
Every now and then, the research report of a huge study comes along.
And by that, I don’t mean that the results have a major impact. Rather, I am referring to the scope and scale of the work effort required to conduct the study. For example, the GIANT study which is looking for genetic variations associated with height (Click here to read a previous SoPD post that briefly touches on that study).
Recently, the report of one huge study was published:
Title: Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State
Authors: Kurnik M, Sahin C, Andersen CB, Lorenzen N, Giehm L, Mohammad-Beigi H, Jessen CM, Pedersen JS, Christiansen G, Petersen SV, Staal R, Krishnamurthy G, Pitts K, Reinhart PH, Mulder FAA, Mente S, Hirst WD, Otzen DE.
Journal: Cell Chem Biol. 2018 Aug 29. pii: S2451-9456(18)30271-X.
In this study, researchers from Arrhus University, Biogen, Amgen, Genentech, Forma Therapeutics, & Alentis Pharma screened almost 750,000 different compounds for their ability to interact with the Parkinsons-associated protein alpha synuclein.
And before we go any further, just take a moment to fully appreciate the size of that number again:
That is eye watering stuff! That is a “I need to sit down for a moment and let this sink in” kind of number. That is a “Are there that many compounds in all of the known universe?” number.
After reading the number, I was left wondering what each of the scientists involved in this study must have been thinking when the boss first said “Hey guys, let’s screen half a million compounds…. no, wait, better yet, why stop there. Let’s make it 3/4 of a million compounds”
How enthusiastic was the “Yes boss” response, I wonder?
All kidding aside, this is an amazing study (and the actual number of compounds screened was only 746,000).
And the researchers who conducted the study should be congratulated on their achievement, as the results of their study may have a profound impact in the longer-term for the Parkinson’s community – you see, the researchers found 58 compounds that markedly inhibited the aggregation of alpha synuclein, as well as another 100 compounds that actually increased its aggregation. A great deal of research will result from this single, remarkable piece of work.
But of particular interest to us here at the SoPD, was the activity of one of the positive control compounds that the researchers used in some of the tests.
What was the control compound?
It is one of the most frequent non-motor features of Parkinson’s and yet it is one of the least publicly discussed.
The word ‘constipation’ is generally used to describe bowel movements that are infrequent or difficult to pass. The stool is often dry, lumpy and hard, and problematic to expel. Other symptoms can include abdominal pain, bloating, and the feeling that one has not completely passed the bowel movement.
In today’s post we look at what can cause constipation, why it may be so common in Parkinson’s, discuss what can be done to alleviate it, and look at clinical trials focused on this issue.
As many as 1 in 5 people say they have suffered from chronic (long-term) constipation at some point in their lives.
It results in more than 2.5 million hospital and physicians visits per year in the USA.
And Americans spend more than $700 million on treatments for it annually (Source).
More importantly, constipation is considered by many researchers to be a risk factor for developing Parkinson’s, as many people in the affected community claim to have experienced constipation for long periods prior to diagnosis.
Why this is, what is being done to research it, and what can be done about constipation in Parkinson’s is the topic of today’s post. But first, let’s start with the obvious question:
What is constipation?