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?
Recently researcher from the University of Cambridge reported that an imbalance in calcium and the Parkinson’s-associated protein alpha synuclein can cause the clustering of synaptic vesicles.
What does this mean? And should we reduce our calcium intake as a result?
In today’s post, we will review the research report, consider the biology behind the findings and how it could relate to Parkinson’s, and discuss what can or should be done.
Me and Brie. Source: Wikipedia
When I turned 25, I realised that my body no longer accepted cheese.
This was a very serious problem.
You see, I still really liked cheese.
A bottle of red wine, a baguette and a chunk of brie – is there any better combination in life?
So obviously my body and I had a falling out. And yes, it got ugly. I wanted things to keep going the way they had always been, so I tried to make things interesting with new and exotic kinds of cheeses, which my body didn’t want to know about it. It rejected all of my efforts. And after a while, I gradually started resenting my body for letting me be who I was.
We sought help. We tried interventions. But sadly, nothing worked.
And then things got really bad: My body decided that it didn’t have room in its life for yogurt, milk or even ice cream anymore (not even ice cream!!!). Basically no dairy what so ever.
There’s something’s missing in my life. Source: Morellisices
OMG. How did you survive without ice cream?
Well, I’ll tell ye – it’s been rough.
All silliness aside though, here is what I know: It is actually very common to develop a lactase deficiency as we get older – lactase being the enzyme responsible for the digestion of whole milk. In fact, about 65% of the global population has a reduced ability to digest lactose after infancy (Source: NIH). I am not lactose intolerant (one of the few tests that I actually aced in my life), but I do have trouble digesting a particular component of dairy products – which can result in discomfort and socially embarrassing situations (one day over a drink I’ll tell you the ‘cheese fondue story’). Curiously, that mystery ingredient is also present in products that have no dairy (such as mayonnaise – it absolutely kills me).
But spare me your tears, if one is forced to drop a particular food group, dairy is not too bad (if I am ever forced to give up wine, I swear I’ll go postal).
My biggest concern when I dropped dairy, however, was “where was I going to get my daily requirements of calcium?“.
Understand that calcium is really rather important.
Why is calcium important?
Here’s a good riddle for you:
Many epidemiological studies have suggested that coffee/caffeine consumption reduces one’s risk of developing Parkinson’s. Study after study has suggested that drinking coffee is beneficial.
Recently, however, Japanese researchers have discovered something really curious: people with Parkinson’s have reduced levels of caffeine in their blood compared to healthy controls… even when they have consumed the same amount of coffee. (???)
In today’s post we will look at what coffee is, review the results of this study, and try to understand what is going on.
Kaldi the goat herder. Source: CoffeeCrossroads
Legend has it that in 800AD, a young Ethiopian goat herder named Kaldi noticed that his animals were “dancing”.
They had been eating some berries from a tree that Kaldi did not recognise, but being a plucky young fellow – and being fascinated by the merry behaviour of his four-legged friends – Kaldi naturally decided to eat some of the berries for himself.
The result: He became “the happiest herder in happy Arabia” (Source).
This amusing encounter was apparently how humans discovered coffee. It is most likely a fiction as the earliest credible accounts of coffee-consumption emerge from the 15th century in the Sufi shrines of Yemen, but since then coffee has gone on to become one of the most popular drinks in the world.
Silly question, but what exactly is coffee?
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
New research published in the last week provides further experimental support for numerous clinical trials currently being conducted, including one by the biotech company Sanofi Genzyme.
Researchers have demonstrated that tiny proteins which usually reside on the outer wall of cells could be playing an important role in the protein clustering (or aggregation) that characterises Parkinson’s.
In today’s post we will look at this new research and discuss what it could mean for the on going clinical trials for Parkinson’s.
The proverb ‘When the cat is away, the mice will play’ has Latin origins.
Dum felis dormit, mus gaudet et exsi litantro (or ‘When the cat falls asleep, the mouse rejoices and leaps from the hole’)
It was also used in the early fourteenth century by the French: Ou chat na rat regne (‘Where there is no cat, the rat is king’).
And then Will Shakespeare used it in Henry the Fifth(1599), Act I, Scene II:
Westmoreland, speaking with King Henry V, Gloucester, Bedford, Exeter and Warwick
“But there’s a saying very old and true,
‘If that you will France win,
Then with Scotland first begin:’
For once the eagle England being in prey,
To her unguarded nest the weasel Scot
Comes sneaking and so sucks her princely eggs,
Playing the mouse in absence of the cat,
To tear and havoc more than she can eat”
Interesting. But what does any of this have to do with Parkinson’s?
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.
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.
Genetic mutations (or ‘variants’) in the Leucine-rich repeat kinase 2 (or LRRK2; also known as Dardarin) gene are associated with increased risk of Parkinson’s. As a result this gene has become the focus of a lot of genetic research.
But what about LRRK2’s less well-known, rather neglected sibling LRRK1?
In today’s post, we will look at new research that suggests the LRRK siblings could both be involved with Parkinson’s disease.
I recommend to the reader that today’s post should be read with the following music playing in the background:
Inspired by a poem of the same title, English composer Ralph Vaughan Williams wrote ‘The Lark Ascending’ in 1914. It is still to this day, a tune that remains a firm favourite with BBC listeners here in the UK (Source).
On to business:
While the music and the poem are about a songbird, today’s SoPD post deals with a different kind of Lark.
Or should I say LRRK.
This is Sergey Brin.
He was one of the founders of a small company you may have heard of – it’s called “Google”.
Having changed the way the world searches the internet, he is now turning his attention to other projects.
One of those other projects is close to our hearts: Parkinson’s disease.
The protein Alpha Synuclein has long been considered the bad-boy of Parkinson’s disease research. Possibly one of the main villains in the whole scheme of things.
New research suggests that it may be interfering with a neuroprotective pathway, leaving the affected cell more vulnerable to stress/toxins. But that same research has highlighted a novel beneficial feature of an old class of drugs: MAO-B inhibitors.
In today’s post we will outline the new research, discuss the results, and look at whether this new Trk warrants a re-think of MAO-B inhibitors.
The great Harry Houdini. Source: Wikipedia
I’m not sure about you, but I enjoy a good magic trick.
That exhilarating moment when you are left wondering just one thing: How do they do that?
(Seriously, at 4:40 a baguette comes out of thin air – how did he do that?)
Widely believed to have been one of the greatest magicians of all time (Source), Harry Houdini is still to this day revered among those who practise the ‘dark arts’.
Born Erik Weisz in Budapest (in 1874), Houdini arrived in the US in 1878. Fascinated with magic, in 1894, he launched his career as a professional magician and drew attention for his daring feats of escape. He renamed himself “Harry Houdini” – the first name being derived from his childhood nickname, “Ehrie,” and the last name paying homage to the great French magician Jean Eugène Robert-Houdin. In 1899, Houdini’s act caught the eye of Martin Beck, an entertainment manager, and from there the rest is history. Constantly upping the ante, his feats became bolder and more death defying.
And the crowds loved him.
From stage, he moved on to film – ultimately starting his own production company, Houdini Picture Corporation. In addition, he was a passionate debunker of psychics and mediums, his training in magic helping him to expose frauds (which turned him against his former friend Sir Arthur Conan Doyle, who believed deeply in spiritualism).
This is all very interesting, but what does any of it have to do with Parkinson’s?
Mitochondrial division inhibitor-1 (mdivi-1) is a small molecule drug that is demonstrating very impressive effects in preclinical models of Parkinson’s disease. With further research it could represent a potential future therapy for people with Parkinson’s disease, particularly those with genetic mutations affecting the mitochondria in their cells.
What are mitochondria?
In this post, we will explain what mitochondria are, how they may be involved in Parkinson’s disease, and we will discuss what the results of new research mean for future therapeutic strategies.
Mitochondria are fascinating.
Utterly. Utterly. Fascinating.
On the most basic level, Mitochondria (mitochondrion, singular; from the Greek words mitos (thread) and chondros (granule)) are just tiny little bean-shaped structures within the cells in our body, and their primary function is to act as the power stations. They supply the bulk of energy that cells require to keep the lights on. This chemical form of energy produced by the mitochondria is called adenosine triphosphate (or ATP). Lots of mitochondria are required in each cell to help keep the cell alive (as is shown in the image below, which is showing just the mitochondria (red) and the nucleus (blue) of several cells).
Lots of mitochondria (red) inside cells (nucleus in blue). Source: Clonetech
That’s the basic stuff – the general definition you will find in most text books on biology.
But let me ask you this:
How on earth did mitochondria come to be inside each cell and playing such a fundamental role?
I don’t know. Are you going to tell me?
Because we simply don’t know.
But understand this: Mitochondria are intruders.