This week multiple research groups at the University of Oxford and Boston-based FORMA Therapeutics announced a collaboration to identify, validate and develop deubiquitinating enzyme (DUB) inhibitors for the treatment of neurodegenerative conditions, like Parkinson’s.
But what exactly are DUB inhibitors? And how do they work?
In today’s post, we will answer these questions, look at what the new collaboration involves, and look at what else is happening with DUB inhibitors for Parkinson’s.
Dubstep is a genre of electronic dance music that originated in South London in the late 1990s. Only recently -in the 2010s – has the culture really become more mainstream. And while I have a hard time appreciating the heavy bass music (man, I am becoming a grumpy old man before my time), it is amazing to watch some of the dancers who robotically embody this form of music:
The guy on the right is named Marquese Scott. Sometimes he simply defies the laws of physics.
The title of today’s post is a play on words, because rather than doing ‘Dubstep’ we are going to be discussing how to ‘DUB-stop’.
Researchers in Oxford have recently signed an agreement with a US company to focus resources and attention on a new approach for tackling neurodegenerative conditions, including Parkinson’s.
What they are proposing is a complicated biological dance.
Their idea: to stop deubiquitinating (DUB) enzymes.
What are deubiquitinating enzymes?
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
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?
Today’s (experimental) post provides something new – an overview of some of the major bits of Parkinson’s-related research that were made available in January 2018.
In January of 2018, the world was rocked by news that New Zealand had become the 11th country in the world to put a rocket into orbit (no really, I’m serious. Not kidding here – Click here to read more). Firmly cementing their place in the rankings of world superpowers. In addition, they became only the second country to have a prime minister get pregnant during their term in office (in this case just 3 months into her term in office – Click here to read more about this).
In major research news, NASA and NOAA announced that 2017 was the hottest year on record globally (without an El Niño), and among the top three hottest years overall (Click here for more on this), and scientists in China reported in the journal Cell that they had created the first monkey clones, named Zhong Zhong and Hua Hua (Click here for that news)
Zhong Zhong the cute little clone. Source: BBC
In 2018, there is one particular clinical trial that I will be watching, because the drug being tested could have a big impact on certain kinds of Parkinson’s.
The clinical trial is focused on people with cancer and they will be treated with a drug called TVB-2640. TVB-2640 is an inhibitor of an enzyme called fatty acid synthase (or FAS).
In today’s post we will discuss why TVB-2640 might be a useful treatment for certain kinds of Parkinson’s.
Mitochondria and their location in the cell. Source: NCBI
Regular readers of this blog are probably getting sick of the picture above.
I use it regularly on this website, because a.) it nicely displays a basic schematic of a mitochondrion (singular), and where mitochondria (plural) reside inside a cell. And b.) a lot of evidence is pointing towards mitochondrial dysfunction in Parkinson’s.
What are mitochondria?
Mitochondria are the power stations of each cell. They help to keep the lights on. Without them, the party is over and the cell dies.
How do they supply the cell with energy?
They convert nutrients from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful (some cells have thousands) and highly organised within the cell, being moved around to wherever they are needed.
What does this have to do with Parkinson’s?
At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective.
2017 has been an incredible year for Parkinson’s research.
And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.
In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)
The number of research reports and clinical trial studies per year since 1817
As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.
The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).
PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.
That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.
And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.
So what happened in 2017? Continue reading
Last week, as everyone was preparing for Christmas celebrations, researchers at the pharmaceutic company Novartis published new research on a gene that is involved with Parkinson’s, called PARKIN (or PARK2).
They used a new gene editing technology – called CRISPR – to conduct a large screening study to identify proteins that are involved with the activation of PARKIN.
In today’s post we will look at what PARKIN does, review the research report, and discuss how these results could be very beneficial for the Parkinson’s community.
As many people within the Parkinson’s community will be aware, 2017 represented the 200th anniversary of the first report of Parkinson’s disease by James Parkinson.
It also the 20th anniversary of the discovery of first genetic mutation (or variant) that increases the risk of developing Parkinson’s. That genetic variation occurs in a region of DNA (a gene) called ‘alpha synuclein’. Yes, that same alpha synuclein that seems to play such a critical role in Parkinson’s (Click here to read more about the 20th anniversary).
In 2018, we will be observing the 20th anniversary of the second genetic variation associated with Parkinson.
That gene is called PARKIN:
Title: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.
Authors: Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N
Journal: Nature. 1998 Apr 9; 392(6676):605-8
In 1998, Japanese researchers published this report based on 5 individuals from 4 Japanese families who were affected by juvenile-onset Parkinson’s. In family 1, the affected individual was a female, 43 years old, born of first-cousin parents, and her two younger brothers are healthy. Her condition was diagnosed in her teens and it had then progressed very slowly afterwards. Her response to L-dopa was very positive, but L-dopa-induced dyskinesia were frequent. In family 2-4, affected individuals (born to unrelated parents) exhibited very similar clinical features to the subject in family 1. The age of onset was between 18 to 27 years of age.
Using previous research and various techniques the investigators were able to isolate genetic variations that were shared between the 5 affected individuals. They ultimately narrowed down their search to a section of DNA containing 2,960 base pairs, which encoded a protein of 465 amino acids.
They decided to call that protein PARKIN.
PARKIN Protein. Source: Wikipedia
How much of Parkinson’s is genetic?
This week Denali Therapeutics released the results of a phase I clinical trial of their primary product, called DNL-201.
DNL-201 is a LRRK2 inhibitor that the company is attempting to take to the clinic for Parkinson’s disease.
In today’s post we will look at what LRRK2 is, how an inhibitor might help in Parkinson’s, and what the results of the trial actually mean.
Denali. Source: Wikipedia
Denali (Koyukon for “the high one”; also known as Mount McKinley) in Alaska is the highest mountain peak in North America, with a summit elevation of 20,310 feet (6,190 m) above sea level. The first verified ascent to Denali’s summit occurred on June 7, 1913, by four climbers Hudson Stuck, Harry Karstens, Walter Harper, and Robert Tatum.
Tatum (left), Karstens (middle), and Harper (right). Source: Gutenberg
Robert Tatum later commented, “The view from the top of Mount McKinley is like looking out the windows of Heaven!”
More recently another adventurous group associated with ‘Denali’ have been trying to scale lofty heights, but of a completely different sort from the mountaineering kind.
In 2017, Parkinson’s UK – the largest charitable funder of Parkinson’s disease research in Europe – took a bold step forward in their efforts to find novel therapies.
In addition to funding a wide range of small and large academic research projects and supporting clinical trials, they have also decided to set up ‘virtual biotech’ companies – providing focused efforts to develop new drugs for Parkinson’s, targeting very specific therapeutic areas.
In today’s post we will look at the science behind their first virtual biotech company: Keapstone.
A virtual world of bioscience. Source: Cast-Pharma
I have previously discussed the fantastic Parkinson’s-related research being conducted at Sheffield University (Click here to read that post). Particularly at the Sheffield Institute for Translational Neuroscience (SITraN) which was opened in 2010 by Her Majesty The Queen. It is the first European Institute purpose-built and dedicated to basic and clinical research into Motor Neuron Disease as well as other neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease.
The research being conducted at the SITraN has given rise to multiple lines of research following up interesting drug candidates which are gradually being taken to the clinic for various conditions, including Parkinson’s.
It’s all very impressive.
And apparently I’m not the only one who thought it was impressive.
There is a protein in most of the cells in your body called “PTEN-induced putative kinase 1″ (or simply PINK1). It plays an important role in keeping your cells healthy.
Genetic variations in the PINK1 gene have been shown to increase ones risk of developing Parkinson’s.
This week researchers have identified a method by which the function of the PINK1 protein can be inhibited and this results in increased vulnerability to Parkinson’s. In this post, we will look at what PINK1 does, how it is inhibited, and what this could mean for the Parkinson’s community.
Mitochondria (green) in health cells (left) and in unhealthy cells (right).
The nucleus of the cell is in blue. Source: Salk Institute
I have previously spoken a lot about mitochondria and Parkinson’s on this website.
For the uninitiated, mitochondria are the power house of each cell. They help to keep the lights on. Without them, the party is over and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
You may remember from high school biology class that mitochondria are tiny bean-shaped objects within the cell. They convert nutrients from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful (some cells have thousands) and highly organised within the cell, being moved around to wherever they are needed.
Like you and I and all other things in life, however, mitochondria have a use-by date.
As mitochondria get old and worn out (or damaged) with time, the cell will recycle them via a process called mitophagy (a blending of the words mitochondria and autophagy which is the waste disposal system of each cell).
What does this have to do with Parkinson’s disease?