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???
In this post I review recently published research describing interesting new gene therapy tools.
“Gene therapy” involved using genetics, rather than medication to treat conditions like Parkinson’s disease. By replacing faulty sections of DNA (or genes) or providing supportive genes, doctors hope to better treat certain diseases.
While we have ample knowledge regarding how to correct or insert genes effectively, the problem has always been delivery: getting the new DNA into the right types of cells while avoiding all of the other cells.
Now, researchers at the California Institute of Technology may be on the verge of solving this issue with specially engineered viruses.
Gene therapy. Source: yourgenome
When you get sick, the usual solution is to visit your doctor. They will prescribe a medication for you to take, and then all things going well (fingers crossed/knock on wood) you will start to feel better. It is a rather simple and straight forward process, and it has largely worked well for most of us for quite some time.
As the overall population has started to live longer, however, we have become more and more exposed to chronic conditions which require long-term treatment regimes. The “long-term” aspect of this means that some people are regularly taking medication as part of their daily lives. In many cases, these medications are taken multiple times per day.
An example of this is Levodopa (also known as Sinemet or Madopar) which is the most common treatment for the chronic condition of Parkinson’s disease. When you swallow your Levodopa pill, it is broken down in the gut, absorbed through the wall of the intestines, transported to the brain via our blood system, where it is converted into the chemical dopamine – the chemical that is lost in Parkinson’s disease. This conversion of Levodopa increases the levels of dopamine in your brain, which helps to alleviate the motor issues associated with Parkinson’s disease.
Levodopa. Source: Drugs
This pill form of treating a disease is only a temporary solution though. People with Parkinson’s disease – like other chronic conditions – need to take multiple tablets of Levodopa every day to keep their motor features under control. And long term this approach can result in other complications, such as Levodopa-induced dyskinesias in the case of Parkinson’s.
Yeah, but is there a better approach?
Some researchers believe there is. But we are not quite there yet with the application of that approach. Let me explain:
Two months ago a research report was published in the scientific journal ‘Nature’ and it caused a bit of a fuss in the embryonic stem cell world.
Embryonic stem (ES) cells are currently being pushed towards the clinic as a possible source of cells for regenerative medicine. But this new report suggested that quite a few of the embryonic stem cells being tested may be carrying genetic variations that could be bad. Bad as in cancer bad.
In this post, I will review the study and discuss what it means for cell transplantation therapy for Parkinson’s disease.
For folks in the stem cell field, the absolute go-to source for all things stem cell related is Prof Paul Knoepfler‘s blog “The Niche“. From the latest scientific research to exciting new stem cell biotech ventures (and even all of the regulatory changes being proposed in congress), Paul’s blog is a daily must read for anyone serious about stem cell research. He has his finger on the pulse and takes the whole field very, very seriously.
For a long time now, Paul has been on a personal crusade. Like many others in the field (including yours truly), he has been expressing concern about the unsavoury practices of the growing direct-to-consumer, stem cell clinic industry. You may have seen him mentioned in the media regarding this topic (such as this article).
The real concern is that while much of the field is still experimental, many stem cell clinics are making grossly unsubstantiated claims to draw in customers. From exaggerated levels of successful outcomes (100% satisfaction rate?) all the way through to talking about clinical trials that simply do not exist. The industry is badly (read: barely) regulated which is ultimately putting patients at risk (one example: three patients were left blind after undergoing an unproven stem cell treatment – click here to read more on this).
While the stem cell research field fully understands and appreciates the desperate desire of the communities affected by various degenerative conditions, there has to be regulations and strict control standards that all practitioners must abide by. And first amongst any proposed standards should be that the therapy has been proven to be effective for a particular condition in independently audited double blind, placebo controlled trials. Until such proof is provided, the sellers of such products are simply preying on the desperation of the people seeking these types of procedures.
One of the most common observations that people make when they attend a Parkinson’s disease support group meeting is the huge variety of symptoms between sufferers.
Some people affected by this condition are more tremor dominant, while others have more pronounced gait (or walking) issues. In addition, some people have an early onset version, while others has a very later onset. What could explain this wide range of features?
A group of Stanford researchers have recently proposed an interesting new idea regarding our understanding of genetics that could partly explain some of this variability. In todays post I speculate on whether their idea could be applied to Parkinson’s disease.
Earlier this year an interesting study was published in the prestigious journal Nature on the topic of the genetics of height (yes height. Trust me, I’m going somewhere with this):
Title: Rare and low-frequency coding variants alter human adult height
Authors: Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu Y, Schurmann C,………at least 200 additional authors have been deleted here in order to save some space…….EPIC-InterAct Consortium; CHD Exome+ Consortium; ExomeBP Consortium; T2D-Genes Consortium; GoT2D Genes Consortium; Global Lipids Genetics Consortium; ReproGen Consortium; MAGIC Investigators, Rotter JI, Boehnke M, Kathiresan S, McCarthy MI, Willer CJ, Stefansson K, Borecki IB, Liu DJ, North KE, Heard-Costa NL, Pers TH, Lindgren CM, Oxvig C, Kutalik Z, Rivadeneira F, Loos RJ, Frayling TM, Hirschhorn JN, Deloukas P, Lettre G.
Journal: Nature. 2017 Feb 9;542(7640):186-190.
In this study, the researchers – who are part of the GIANT consortium – were analysing DNA collected from over 700,000 people and trying to determine what genetic differences could influence height.
Height is not important for music. Source: Imgur
Why study height?
Good question. There are several reasons:
Firstly, it is easy to accurately measure. Second, the researchers believed that if we can master the complex genetics of something simple like height maybe what we learn will give us a blueprint for how we should study more complex medical disorders that have thus far eluded our complete understanding.
On the 27th June, 1997, a research report was published in the prestigious scientific journal ‘Science’ that would change the world of Parkinson’s disease research forever.
And I am not exaggerating here.
The discovery that genetic variations in a gene called alpha synuclein could increase the risk of developing Parkinson’s disease opened up whole new areas of research and eventually led to ongoing clinical trials of potential therapeutic applications.
Todays post recounts the events surrounding the discovery, what has happened since, and we will discuss where things are heading in the future.
It is fair to say that 1997 was an eventful year.
In world events, President Bill Clinton was entering his second term, Madeleine Albright became the first female Secretary of State for the USA, Tony Blair became the prime minister of the UK, and Great Britain handed back Hong Kong to China.
#42 – Bill Clinton. Source: Wikipedia
In the world of entertainment, author J. K. Rowling’s debut novel “Harry Potter and the Philosopher’s Stone” was published by Bloomsbury, and Teletubbies, South Park, Ally McBeal, and Cold Feet (it’s a British thing) all appeared on TV for the first time, amusing and entertaining the various age groups associated with them.
South Park. Source: Hollywoodreporter
Musically, rock band Blur released their popular hit song ‘Song 2‘ (released 7th April), “Bitter Sweet Symphony” by the Verve entered the UK charts at number 2 in June, and rapper Notorious B.I.G. was killed in a drive by shooting. Oh, and let’s not forget that “Tubthumping” (also known as “I Get Knocked Down”) by Chumbawamba was driving everybody nuts for its ubiquitous presence.
And at the cinemas, no one seemed to care about anything except a silly movie called Titanic.
Titanic. Source: Hotspot
Feeling old yet?
In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.
This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.
The first issue of Nature. Source: SimpleWikipedia
The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).
Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!
On the 21st June, this report was published:
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).
What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.
In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.
The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.
This is Lysimachos.
Pronounced: “Leasing ma horse (without the R)” – his words not mine.
He is one of the founders of an Edinburgh-based biotech company called “Parkure“.
In today’s post, we’ll have a look at what the company is doing and what it could mean for Parkinson’s disease.
The first thing I asked Dr Lysimachos Zografos when we met was: “Are you crazy?”
Understand that I did not mean the question in a negative or offensive manner. I asked it in the same way people ask if Elon Musk is crazy for starting a company with the goal of ‘colonising Mars’.
In 2014, Lysimachos left a nice job in academic research to start a small biotech firm that would use flies to screen for drugs that could be used to treat Parkinson’s disease. An interesting idea, right? But a rather incredible undertaking when you consider the enormous resources of the competition: big pharmaceutical companies. No matter which way you look at this, it has the makings of a real David versus Goliath story.
But also understand this: when I asked him that question, there was a strong element of jealousy in my voice.
Incorporated in October 2014, this University of Edinburgh spin-out company has already had an interesting story. Here at the SoPD, we have been following their activities with interest for some time, and decided to write this post to make readers aware of them.