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?
This week Austrian biotech firm, AFFiRiS AG, made an announcement regarding their experimental immunotherapy/’vaccine’ approach for Parkinson’s.
In their press release, the company provided the results of a long-term Phase I clinical trial testing the tolerability and safety of their treatment AFFITOPE® PD01A.
The treatment was found to be safe and well-tolerated in people with Parkinson’s. But there was one sentence which was particularly intriguing in the press release regarding clinical symptoms.
In today’s post, we will discuss what is meant by ‘immunotherapy’, outline what this particular clinical trial involved, review the results, and explore what this could mean for the Parkinson’s community.
I have previously mentioned on this website that any ‘cure for Parkinson’s’ is going to require three components:
- A disease halting mechanism
- A neuroprotective agent
- Some form of cell replacement therapy
This week we got some interesting clinical news regarding the one of these components: A disease halting mechanism
Clinical trial results from Austria suggest that a new immunotherapy approach in people with Parkinson’s is both safe and well tolerated over long periods of time.
What is immunotherapy?
On this website, we regularly talk about a Parkinson’s-associated protein called Alpha Synuclein.
It is widely considered to be ‘public enemy #1’ in the world of Parkinson’s research, or at the very least one of the major ‘trouble makers’. It is a curious little protein – one of the most abundant proteins in your brain.
But did you know that there are different ‘species’ of alpha synuclein?
And recently researchers in Florida announced that they had identified an all new species of alpha synuclein that they have called “P-alpha-syn-star” or Pα-syn*.
In today’s post, we will discuss what is meant by the word ‘species’, look at the different species of alpha synuclein, and explore what this new species could mean for the Parkinson’s community.
This microscopic creature is called Macrobiotus shonaicus.
Isn’t it cute?
The researchers that discovered it found it in a Japanese parking lot.
It is one of the newest species of life discovered to date (Click here for the research report). It is a species of Tardigrade (meaning “slow stepper”; also known as a water bear or moss piglet). And for the uninitiated: Tardigrade are remarkable creatures.
Tardigrade. Source: BBC
They measure just 0.5 mm (0.02 in) long, there are approximately 1,150 known species of them, and they have been around for a VERY long time – with fossil records dating back to the Cambrian period (500 million years ago).
The tree of life (try and find the dinosaurs). Source: Evogeneao
But most importantly, tardigrade are EXTREMELY resilient:
- they are the first known animals to survive in hard vacuum and UV radiation of outer space. Some of them can withstand extreme cold – down to temperatures of −458 °F (−272 °C), while other species of Tardigrade can withstand extremely hot temperatures – up to 300 °F (150 °C) (Click here to read more)
- they can withstand 1,000 times more radiation than other animals (Click here for more on that)
- some species of Tardigrade can also withstand pressure of 6,000 atmospheres (that is nearly SIX times the pressure of water in the deepest ocean trench – the Mariana trench! Click here for more on this)
- They are one of the few groups of species that are capable of suspending their metabolism; surviving for more than 30 years at −20 °C (−4 °F – Click here to read about this)
They are utterly remarkable creatures.
Great, but what does this have to do with Parkinson’s? Continue reading
At the end of each month, the Science of Parkinson’s writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available.
In this post we review some of the research from February 2018.
The post is divided into four parts based on the type of research (Basic biology, disease mechanism, clinical research, and other news).
Seeing shadows: Punxsutawney Phil. Source: Wordonfire
In major world event news: On the 2nd February of 2018, Punxsutawney Phil – the groundhog who resides at Gobbler’s Knob of Punxsutawney, Pennsylvania – scurried out of his little hole and saw his shadow. This omen indicates that we have a long winter. Given how hard and bitter this particular winter has been, Americans naturally rejoiced.
On the 6th February, SpaceX successfully launched a Tesla sports car into space – see the video below for the highlights (and if you don’t have time to watch it all, at the very least jump forward to 3:45 and watch the two boosters land simultaneously – surely they didn’t plan for it to be that perfect!)
In other news, on the 1st February, the Centers for Disease Control and Prevention announced that it was dramatically downsizing its epidemic prevention activities in 39 out of 49 countries, due to concerns about funding.
And of course we had the 2018 Winter Olympics – where New Zealand came in 27th on the medals board:
In the world of Parkinson’s research, a great deal of new research and news was reported.
In February 2018, there were 698 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (1577 for all of 2018 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).
The top 5 pieces of PD news
An Advanced Glycation Endproduct (or AGE) is a protein or lipid that has become glycated.
Glycation is a haphazard process that impairs the normal functioning of molecules. It occurs as a result of exposure to high amounts of sugar. These AGEs are present at above average levels in people with diabetes and various ageing-related disorders, including neurodegenerative conditions. AGEs have been shown to trigger signalling pathways within cells that are associated with both oxidative stress and inflammation, but also cell death.
RAGE (or receptor of AGEs) is a molecule in a cell membrane that becomes activated when it interacts with various AGEs. And this interaction mediates AGE-associated toxicity issues. Recently researchers found that that neurons carrying the Parkinson’s associated LRRK2 G2019S genetic variant are more sensitive to AGEs than neurons without the genetic variant.
In today’s post we will look at what AGE and RAGE are, review the new LRRK2 research, and discuss how blocking RAGE could represent a future therapeutic approach for treating Parkinson’s.
The wonder of ageing. Source: Club-cleo
NOTE: Be warned, the reading of this post may get a bit confusing. We are going to be discussing ageing (as in the body getting old) as well as AGEing (the haphazard process processing of glycation). For better clarification, lower caps ‘age’ will refer to getting old, while capitalised ‘AGE’ will deal with that glycation process. I hope this helps.
Ageing means different things to different people.
For some people ageing means more years to add to your life and less activity. For others it means more medication and less hair. More wrinkles and less independence; more arthritis and less dignity; More candles, and less respect from that unruly younger generation; More… what’s that word I’m thinking of? (forgetfulness)… and what were we actually talking about?
Wisdom is supposed to come with age, but as the comedian/entertainer George Carlin once said “Age is a hell of a price to pay for wisdom”. I have to say though, that if I had ever met Mr Carlin, I would have suggested to him that I’m feeling rather ripped off!
George Carlin. Source: Thethornycroftdiatribe
Whether we like it or not, from the moment you are born, ageing is an inevitable part of our life. But this has not stopped some adventurous scientific souls from trying to understand the process, and even try to alter it in an attempt to help humans live longer.
Regardless of whether you agree with the idea of humans living longer than their specified use-by-date, some of this ageing-related research could have tremendous benefits for neurodegenerative conditions, like Parkinson’s.
What do we know about the biology of ageing?
For a long time researchers have lacked truly disease-relevant models of Parkinson’s.
We have loaded cells with toxins to cause cell death, we have loaded cells with mutant proteins to cause cell death, we have loaded cells with… well, you get the idea. Long story short though, we have never had proper models of Parkinson’s – that is a model which present all of the cardinal features of the condition (Lewy bodies, cell loss, and motor impairment).
The various models we have available have provided us with a wealth of knowledge about the biology of how cells die and how we can protect them, which has led to numerous experimental drugs being tested in the clinic. But there has always been a linger question of ‘how disease-relevant are these models?’
This situation may be about to change.
In today’s post we will look at new research in which Japanese researchers have genetically engineered mice in which they observed the generation of Lewy bodies, the loss of dopamine neurons and motor impairments. We will look at how these mice have been generated, and what it may tell us about Parkinson’s.
Walt Disney. Source: PBS
Ok, before we start today’s post: Five interesting facts about the animator Walt Disney (1901 – 1966):
- Disney dropped out of high school at age 16 with the goal of joining the Army to help out in the war effort. He was rejected for being underage, but was able to get a job as an ambulance driver with the Red Cross in France.
- From 1928 (the birth of Mickey Mouse) until 1947, Disney himself performed the voice of Mickey.
- Mickey Mouse was originally named “Mortimer Mouse”, but it was Disney’s wife who suggested that the name Mortimer sounded too pompous (seriously, can you imagine a world with the “Mortimer Mouse show”?). She convinced Disney to change the name to Mickey (the name Mortimer was later given to one of Mickey’s rivals).
- To this day, Disney holds the record for the most individual Academy Awards and nominations. Between 1932 and 1969, he won 22 Academy Awards and was nominated 59 times (Source).
- And best of all: On his deathbed as he lay dying from lung cancer, Disney wrote the name “Kurt Russell” on a piece of paper. They were in effect his ‘last words’. But no one knows what they mean. Even Kurt is a bit perplexed by it all. He (along with many others) was a child actor contracted to the Disney company at the time, but why did Walt write Russell’s name as opposed to something more deep and meaningful (no disrespect intended towards Mr Russell).
Actor Kurt Russell. Source: Fxguide
When asked why he thought his great creation “Mickey mouse” was so popular, Walt Disney responded that “When people laugh at Mickey Mouse, it’s because he’s so human; and that is the secret of his popularity”.
Mickey Mouse. Source: Ohmy.Disney
This is a curious statement.
Curious because in biomedical research, mice are used in experiments to better understand the molecular pathways underlying basic biology and for the testing of novel therapeutics, and yet they are so NOT human.
There are major biological differences between us and them.
Not human. Source: USNews
It has been a major dilemma for the research community for some time with regards to translating novel therapies to humans, and it raises obvious ethical questions of whether we should be using mice at all for the basic research if they are so different from us. This problem is particularly apparent in the field of immunology, where the differences between ‘mice and men’ is so vast in some cases that researcher have called for moving away from mice entirely and focusing on solely human models (Click here and here for a good reads on this topic).
What does this have to do with Parkinson’s?
Last year at the Intel International Science and Engineering Fair, a young high school student named Jeremiah Pate (Image above) took first Place in his category and third prize overall in the Dudley R. Herschbach Stockholm International Youth Science Seminar Award.
This competition involved nearly seven million high school students from all over the world. And by being a winner in the competition, Jeremiah received an all expenses paid trip to attend the Nobel Prize Awards in Stockholm Sweden.
Jeremiah’s award winning project was about his efforts to find a possible cure for Parkinson’s.
In today’s post we will look at the interesting story of how Jeremiah became interested in Parkinson’s and discuss why impatience is a virtue.
We all like stories that involve something bold.
The moon-shot. The last stand against impossible odds. The underrated boxer beating the champ. The enthusiasts putting Gossamer satellites into space. Big-obstacle-being-overcome, that sort of stuff.
I personally really like those stories about individuals with a very specific goal and the determination to let nothing stand between them and achieving it. Those folks who are not satisfied with the status quo and want to change things for the better. Here at the SoPD, we have previously tried to highlight individuals like this within the Parkinson’s research community (for example, Dr Lysimachos Zografos and Sara (soon to be Dr) Riggare). And in keeping with that tradition, today’s post is about a similar individual.
His name is Jeremiah.
And the story begins at the First Baptist Church in Mammoth, Arizona.
The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter).
At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.
2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).
In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.
Charlie Munger (left) and Warren Buffett. Source: Youtube
Many readers will be familiar with the name Warren Buffett.
The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.
Warren Buffett. Source: Quickmeme
He regularly provides great one liners like:
“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”
“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”
“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”
Mr Buffett is wise and a very likeable chap.
Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.
In Silicon valley (California), everyone is always looking for the “next killer app” – the piece of software (or application) that is going to change the world. The revolutionary next step that will solve all of our problems.
The title of today’s post is a play on the words ‘killer app’, but the ‘app’ part doesn’t refer to the word application. Rather it relates to the Alzheimer’s disease-related protein Amyloid Precursor Protein (or APP). Recently new research has been published suggesting that APP is interacting with a Parkinson’s disease-related protein called Leucine-rich repeat kinase 2 (or LRRK2).
The outcome of that interaction can have negative consequences though.
In today’s post we will discuss what is known about both proteins, what the new research suggests and what it could mean for Parkinson’s disease.
Seattle. Source: Thousandwonders
In the mid 1980’s James Leverenz and Mark Sumi of the University of Washington School of Medicine (Seattle) made a curious observation.
After noting the high number of people with Alzheimer’s disease that often displayed some of the clinical features of Parkinson’s disease, they decided to examined the postmortem brains of 40 people who had passed away with pathologically confirmed Alzheimer’s disease – that is, an analysis of their brains confirmed that they had Alzheimer’s.
What the two researchers found shocked them:
Title: Parkinson’s disease in patients with Alzheimer’s disease.
Authors: Leverenz J, Sumi SM.
Journal: Arch Neurol. 1986 Jul;43(7):662-4.
Of the 40 Alzheimer’s disease brains that they looked at nearly half of them (18 cases) had either dopamine cell loss or Lewy bodies – the characteristic features of Parkinsonian brain – in a region called the substantia nigra (where the dopamine neurons are located). They next went back and reviewed the clinical records of these cases and found that rigidity, with or without tremor, had been reported in 13 of those patients. According to their analysis 11 of those patients had the pathologic changes that warranted a diagnosis of Parkinson’s disease.
And the most surprising aspect of this research report: Almost all of the follow up studies, conducted by independent investigators found exactly the same thing!
It is now generally agreed by neuropathologists (the folks who analyse sections of brain for a living) that 20% to 50% of cases of Alzheimer’s disease have the characteristic round, cellular inclusions that we call Lewy bodies which are typically associated with Parkinson disease. In fact, in one analysis of 145 Alzheimer’s brains, 88 (that is 60%!) had chemically verified Lewy bodies (Click here to read more about that study).
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
Oh, and if you are wondering whether this is just a one way street, the answer is “No sir, this phenomenon works both ways”: the features of the Alzheimer’s brain (such as the clustering of a protein called beta-amyloid) are also found in many cases of pathologically confirmed Parkinson’s disease (Click here and here to read more about this).
So what are you saying? Alzheimer’s and Parkinson’s disease are the same thing???
The clustering of a protein called alpha synuclein is one of the cardinal features of the brain of a person with Parkinson’s disease.
Recently published research has demonstrated that tiny antibodies (called nanobodies) derived from llamas (yes, llamas) are very effective at reducing this clustering of alpha synuclein in cell culture models of Parkinson’s disease.
In today’s post, we will discuss the science, review the research and consider what it could all mean for Parkinson’s disease.
Llama. Source: Imagesanimals
Ok, I confess: This post has been partly written purely because I really like llamas. And I’m not ashamed to admit it either.
I mean, look at them! They are fantastic:
Very cute. But what does this have to do with Parkinson’s disease?
Indeed. Let’s get down to business.
This post has also been written because llamas have a very interesting biological characteristic that is now being exploited in many areas of medical research, including for Parkinson’s disease.