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?
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?
The motor features of Parkinson’s disease can be managed with treatments that replace the chemical dopamine in the brain.
While there are many medically approved dopamine replacement drugs available for people affected by Parkinson’s disease, there also are more natural sources.
In today’s post we will look at the science and discuss the research supporting one of the most potent natural source for dopamine replacement treatment: Mucuna pruriens
When asked by colleagues and friends what is my ‘plan B’ (that is, if the career in academia does not play out – which is highly probable I might add – Click here to read more about the disastrous state of biomedical research careers), I answer that I have often considered throwing it all in and setting up a not-for-profit, non-governmental organisation to grow plantations of a tropical legume in strategic places around the world, which would provide the third-world with a cheap source of levodopa – the main treatment in the fight against Parkinson’s disease.
Plan B: A legume plantation. Source: Tropicalforages
The response to my answer is generally one of silent wonder – that is: me silently wondering if they think I’m crazy, and them silently wondering what on earth I’m talking about.
As romantic as the concept sounds, there is an element of truth to my Plan B idea.
I have read many news stories and journal articles about the lack of treatment options for those people with Parkinson’s disease living in the developing world.
Hospital facilities in the rural Africa. Source: ParkinsonsLife
Some of the research articles on this topic provide a terribly stark image of the contrast between people suffering from Parkinson’s disease in the developing world versus the modernised world. A fantastic example of this research is the work being done by the dedicated researchers at the Parkinson Institute in Milan (Italy), who have been conducting the “Parkinson’s disease in Africa collaboration project”.
The researchers at the Parkinson Institute in Milan. Source: Parkinson Institute
The project is an assessment of the socio-demographic, epidemiological, clinical features and genetic causes of Parkinson’s disease in people attending the neurology out-patients clinic of the Korle Bu Teaching and Comboni hospitals. Their work has resulted in several really interesting research reports, such as this one:
Title: The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa.
Authors: Cilia R, Akpalu A, Sarfo FS, Cham M, Amboni M, Cereda E, Fabbri M, Adjei P, Akassi J, Bonetti A, Pezzoli G.
Journal: Brain. 2014 Oct;137(Pt 10):2731-42.
PMID: 25034897 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers collected data in Ghana between December 2008 and November 2012, and each subject was followed-up for at least 6 months after the initiation of Levodopa therapy. In total, 91 Ghanaians were diagnosed with Parkinson’s disease (58 males, average age at onset 60 ± 11 years), and they were compared to 2282 Italian people with Parkinson’s disease who were recruited during the same period. In long-term follow up, 32 Ghanaians with Parkinson’s disease were assessed (with an average follow period of 2.6 years).
There are some interesting details in the results of the study, such as:
- Although Levodopa therapy was generally delayed – due to availability and affordability – in Ghana (average disease duration before Levodopa treatment was 4.2 years in Ghana versus just 2.4 years in Italy), the actual disease duration – as determined by the occurrence of motor fluctuations and the onset of dyskinesias – was similar in the two populations.
- The motor fluctuations were similar in the two populations, with a slightly lower risk of dyskinesias in Ghanaians.
- Levodopa daily doses were higher in Italians, but this difference was no longer significant after adjusting for body weight.
- Ghanaian Parkinson’s sufferers who developed dyskinesias were younger at onset than those who did not.
Reading these sorts of research reports, I am often left baffled by the modern business world’s approach to medicine. I am also left wondering how an individual’s experience of Parkinson’s disease in some of these developing nations would be improved if a cheap alternative to the dopamine replacement therapies was available.
Are any cheap alternatives available?
Something different for you today – a history lesson…with some science.
The history of Parkinson’s disease dates back well before Dr James Parkinson made his observations about 6 patients 199 years ago (oh, big anniversary coming up! Who knew)
But it may surprise you to know that the history of Parkinson’s disease dates back before even Jesus turned up.
You actually have to go back a long back in order to get to the beginning…
If you were demonstrating the early features of Parkinson’s disease in the year 500 BCE, there was really only one place in the world that you wanted to be:
India. Source: blogs.umb.edu
Not only did India have a extremely sophisticated system of diagnosis for what we call Parkinson’s disease, but they also have a VERY effective treatment!
Don’t believe me? Read on.
Around 5000 BCE, the wise and farsighted members of the Indian medical establishment began pooling their collective knowledge – firstly in an oral form, but then eventually in a written format. That written material became the text known as the Ayurveda (/aɪ.ərˈveɪdə/; Sanskrit for “the science of life” or “Life-knowledge”).
It can not be understated how sophisticated the Ayurveda was for its time. This was a period bridging the ‘new stone age’ and the ‘Bronze age’. People’s understanding of medical afflictions was basically limited to what the Gods and evil spirits were doing to them.
The earliest account of Parkinson’s disease features in the Ayurveda was compiled by Susruta (the 600 BC author of “Susruta Samhita”). He described slowness (cestasanga in Sanskrit) and akinesia (cestahani) in certain individuals, and also (curiously) reported that certain poisons could cause rigidity and tremor.
To demonstrate to you just how sophisticated the Ayurveda was, consider this: when faced with a person exhibiting tremor a practitioner using the Ayurveda could chose between six different types of tremor:
- Vepathu (a generalised tremor)
- Prevepana (excessive shaking)
- Kampa vata (tremors due to vata)
- Sirakampa (head tremor)
- Spandin (quivering)
- Kampana (tremors)
Number 3 (Kampa vata) on that list is what we now refer to as Parkinson’s disease. Kampa basically means ‘tremor’, while Vata is more difficult to define – it is essentially the property/force that governs all movement in the mind and body (blood flow, breathing, etc – even the movement of thoughts).
Since the 3rd century BCE, practitioner of the Ayurveda have been using the seeds of Mucuna pruriens in treating conditions of tremor.
Mucuna Prurien seeds. Source: Kisalaya
Authors: Damodaran M, Ramaswamy R.
Journal: Biochem J. 1937 Dec;31(12):2149-52. No abstract available.
PMID: 16746556 (this article is OPEN ACCESS and available to read if you would like)
Authors: Katzenschlager R, Evans A, Manson A, Patsalos PN, Ratnaraj N, Watt H, Timmermann L, Van der Giessen R, Lees AJ.
Journal: J Neurol Neurosurg Psychiatry. 2004 Dec;75(12):1672-7.
PMID: 15548480 (this report is OPEN ACCESS if you would like to read it)