The clustering (or aggregation) of misfolded proteins is a key feature of many neurodegenerative conditions. These aggregating proteins are collectively referred to as ‘amyloid’ proteins, and the way that they have misfolded allows many copies of these proteins to stick together.
Amyloid proteins are associated with more than 50 medical conditions (from Alzheimer’s, ALS, Huntinton’s and Parkinson’s through to rheumatoid arthritis and diabetes).
In addition to being public enemy no. 1 for their respective conditions, amyloid proteins also share another curious feature:
They glow when exposed to specific wavelengths of light (like near-infrared).
In today’s post, we will look at what we mean by ‘amyloid proteins’, what this new research found, and how this property could be extremely useful in the tracking of Parkinson’s over time.
If you have recently sent me an email, you may not have had a response. I apologise profusely for this, but I have gradually become inundated with questions and requests, and have had a hard time keeping up (in addition: family and day job take priority).
I do get some wonderfully titled emails though, which immediately grab the attention.
For example, the other day I recieved an email entitled:
“So, will my head glow in a disco?”
A brief glance at the contents confirmed suspicions that the sender was referring to this new research report:
Title: Ultraviolet–visible–near-infrared optical properties of amyloid fibrils shed light on amyloidogenesis
Authors: Pansieri J, Josserand V, Lee S-J, Rongier A, Imbert D, Sallanon MM, Kövari E, Dane TG, Vendrely C, Chaix-Pluchery O, Guidetti M, Vollaire J, Fertin A, Usson Y, Rannou P, Coll J-L, Marquette C, & Forge V
Journal: Nature Photonics, published 13th May 2019
Previously researchers have described an intrinsic ultraviolet–visible optical property to amyloid proteins.
What does that mean?
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.
Researchers at the University of Cambridge have published an interesting research report last week regarding a clinically available drug that they suggest boosts autophagy in the brain.
Autophagy is one of several processes that cells use to dispose of waste and old proteins.
The drug is called Felodipine, and it is a calcium channel blocker that is used to treat high blood pressure.
In today’s post, we will look at what autophagy is, how boosting it could help with neurodegenerative conditions, and whether Felodipine should be clinically tested for re-purposing to Parkinson’s.
Prof Rubinsztein is the Deputy Director of the CIMR, the Academic Lead of the UK Alzheimer’s Research UK Cambridge Drug Discovery Institute, and he is a group leader at the UK Dementia Research Institute at the University of Cambridge.
He is also one of the world’s leading experts in the field of autophagy in neurodegenerative conditions.
What is autophagy?
Nuclear receptor related 1 protein (or NURR1) is a protein that has been shown to have a powerful effect on the survival of dopamine neurons – a population of cells in the brain that is severely affected by Parkinson’s.
For a long time researchers have been searching for compounds that would activate NURR1, but the vast majority of those efforts have been unsuccessful, leaving some scientists suggesting that NURR1 is “undruggable” (meaning there is no drug that can activate it).
Recently, however, a research report was published which suggests this “undruggable” protein is druggable, and the activator is derived from a curious source: dopamine
In today’s post, we will discuss what NURR1 is, what the new research suggests, and how this new research could be useful in the development of novel therapeutics for Parkinson’s.
It always seems impossible until it’s done – Nelson Mandela
In 1997, when Nelson Mandela was stepping down as President of the African National Congress, some researchers in Stockholm (Sweden) published the results of a study that would have a major impact on our understanding of how to keep dopamine neurons alive.
(Yeah, I know. That is a strange segway, but some of my recent intros have dragged on a bit – so let’s just get down to business)
Dopamine neurons are of the one groups of cells in the brain that are severely affected by Parkinson’s. By the time a person begins to exhibit the movement symptoms of the condition, they will have lost 40-60% of the dopamine neurons in a region called the substantia nigra. In the image below, there are two sections of brain – cut on a horizontal plane through the midbrain at the level of the substantia nigra – one displaying a normal compliment of dopamine neurons (on the left) and the other from a person who passed away with Parkinson’s demonstrating a reduction in this cell population (on the right).
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinsonian brain (right). Source:Memorangapp
The researchers in Sweden had made an amazing discovery – they had identified a single gene (a specific region of DNA) that was critical to the survival of dopamine neurons. When they artificially disrupted the section of DNA where this gene lives – an action which resulted in no protein for this gene being produced – it resulted in mice being born with no midbrain dopamine neurons:
Title: Dopamine neuron agenesis in Nurr1-deficient mice
Authors: Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T.
Journal: Science. 1997 Apr 11;276(5310):248-50.
The researchers who conducted this study found that the mice with no NURR1 protein exhibited very little movement and did not survive long after birth. And this result was very quickly replicated by other independent research groups (Click here and here to see examples)
So what was this amazing gene called?
Nuclear receptor related 1 protein (or NURR1; it is also known as NR4A2 – nuclear receptor subfamily 4, group A, member 2)
And what is NURR1?
It is often said that Parkinson’s is a ‘distinctly human’ condition. Researchers will write in their reports that other animals do not naturally develop the features of the condition, even at late stages of life.
But how true is this statement?
Recently, some research has been published which brings into question this idea.
In today’s post, we will review these new findings and discuss how they may provide us with a means of testing both novel disease modifying therapies AND our very notion of what Parkinson’s means.
Checking his Tinder account? Source: LSE
Deep philosphical question: What makes humans unique?
Seriously, what differentiates us from other members of the animal kingdom?
Some researchers suggest that our tendency to wear clothes is a uniquely human trait.
The clothes we wear make us distinct. Source: Si-ta
But this is certainly not specific to us. While humans dress up to ‘stand out’ in a crowd, there are many species of animals that dress up to hide themselves from both predator and prey.
A good example of this is the ‘decorator crab’ (Naxia tumida; common name Little seaweed crab). These creatures spend a great deal of time dressing up, by sticking stuff (think plants and even some sedentary animals) to their exoskeleton in order to better blend into their environment. Here is a good example:
Many different kinds of insects also dress themselves up, such as Chrysopidae larva:
Dressed for success. Source: Bogleech
In fact, for most of the examples that people propose for “human unique” traits (for example, syntax, art, empathy), mother nature provides many counters (Humpback whales, bower birds, chickens – respectively).
So why is it that we think Parkinson’s is any different?
Wait a minute. Are there other animals that get Parkinson’s?
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?