At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during April 2019.
The post is divided into seven parts based on the type of research:
So, what happened during April 2019?
In world news:
10th April – Scientists from the Event Horizon Telescope project announced the first ever image of a black hole. Located in the core of the Messier 87 galaxy (53 million light years from Earth), this supermassive black hole has a mass 6.5-billion times that of the Sun! The black hole’s boundary – the event horizon – is around 2.5 times smaller than the shadow it casts and measures just under 40 billion km across (about the size of Neptune’s orbit!!!).
10th April – Fossil fragments found in the Callao Cave in the Philippines revealled the existence of a new species of human, Homo luzonensis. The species is named after the island – Luzon – where it was discovered.
15th April – During Holy Week, a devastating fire engulfed the roof and main spire of Notre-Dame Cathedral in Paris.
24th April – I am a big fan of Martin. Several years ago his video of the Marble machine took the internet by storm and since then I have been following his regular vlog updates on the construction of the new and improved Marble machine X. This week he took the new machine for its first test run – still has parts missing, but this is mesmerising to watch. If you don’t follow him you should!
In the world of Parkinson’s research, a great deal of new research and news was reported:
In April 2019, there were 730 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (3134 for all of 2019 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 9 pieces of Parkinson’s news
Microglia are the resident immune cells in the brain – they maintain law and order when trouble kicks off. And when things get really bad, these cells change shape, become “activated”, and start to absorb toxins, debris and anything else that they feel should not be there – via a process called phagocytosis.
And they are ruthless in this task.
When we are young, these cells function very well at maintaining a general sense of ‘homeostasis‘ (or stable equilibrium). But as we age,… well, let’s just say things start to slip a little.
Recently a group of researchers at Stanford University have discovered by inhibiting a single protein, called CD22, they can restore microglial homeostasis in the ageing brain, and this had beneficial effects in a model of Parkinson’s.
In today’s post, we will look at what microglia are, what phagocytosis is, and what these new CD22 results could mean for Parkinson’s.
My father often says: Ageing is not for sissies.
And as the birthdays have started to mount up, I’ve come to better understand what he means.
There are days when I feel like an old man trapped in a 27 year old’s body. For the record, I’m 27. And for the record, I’m going to be 27 until I die (27 was a great year!).
An amazing journey. Source: Topsimages
While some are able (and foolishly gleeful) to avoid taxes, until recently no one has been able to escape the rentless march of ageing. Until recently, the vast majority of us have been resigned to our fates. And until recently, the fountain of youth has only existed in the realm of the Hollywood movies.
The force is strong with this one. Source: Reddit
Recently there has been an enormous amount of research focused on stopping ageing and preventing death (both of which are being viewed as “curable diseases” – click here to read more about this). Now to be honest, much of this is still quackery.
But there does seem to be progress being made in the biology of extending ‘healthspan’ (as opposed to lifespan).
And some of that research could have implications for Parkinson’s.
Researchers at the University of Cambridge have published an interesting research report last week regarding a clinically available drug that they suggest boosts autophagy in the brain.
Autophagy is one of several processes that cells use to dispose of waste and old proteins.
The drug is called Felodipine, and it is a calcium channel blocker that is used to treat high blood pressure.
In today’s post, we will look at what autophagy is, how boosting it could help with neurodegenerative conditions, and whether Felodipine should be clinically tested for re-purposing to Parkinson’s.
Prof Rubinsztein is the Deputy Director of the CIMR, the Academic Lead of the UK Alzheimer’s Research UK Cambridge Drug Discovery Institute, and he is a group leader at the UK Dementia Research Institute at the University of Cambridge.
He is also one of the world’s leading experts in the field of autophagy in neurodegenerative conditions.
What is autophagy?
Glial cell-line derived neurotrophic factor (or GDNF) has been a topic of heated discussion in the Parkinson’s community for a long time. Most recently due to the announcement of the results of the Phase II Bristol GDNF clinical trial results, which did not meet the primary end points of the study (Click here to read more about that).
This week at the annual American Association of Neurological Surgeons conference in San Diego, the results of another GDNF clinical trial were presented.
This new study was a Phase I study assessing the safety and tolerability of a gene therapy approach for GDNF in people with Parkinson’s.
In today’s post, we will discuss what gene therapy is, what the new trial results indicate, and what the researchers may be planning to do next for this new clinical trial programme.
Every year members of the American Association of Neurological Surgeons gather together in one spot and compare data/research/clinical notes.
This year the 87th AANS Annual Scientific Meeting was held in spectacular San Diego.
San Diego. Source: AFP
From Saturday 13th April through till Wednesday 17th, clinicians and researchers attended lectures and discussed new data on every aspect of neurological surgery. While I did not (nor planned to) attend the meeting, I was very interested to learn more about one particular presentation.
It involved the announcement of the results of a clinical trial which was focused on a gene therapy approach for Parkinson’s.
The treatment involved GDNF (Click here to read the abstract).
What is GDNF?
One of the characteristic features of Parkinson’s is the loss of dopamine neurons in the brain. One experimental approach that is being explored for treating the condition involves investigating biological pathways involved in the early development of dopamine neurons.
By re-exposing the dopamine neurons to supportive, growth-encouraging proteins that are present during early development (but absent or reduced in adulthood), researchers hope to be able to rejeuvinate these cells and make them healthier.
In a recent post, we discussed one such developmental supportive protein: Glial cell derived neurotrophic factor (Click here to read more about this).
In today’s post, we will look at a different type of developmental protein which is having interesting effects in models of Parkinson’s. That protein is called Sonic Hedgehog.
The humble fly (Drosophila). Source: Ecolab
No one should ever be allowed to say that fly genetists don’t have a sense of humour.
When it comes to the naming of genes, they have had a great deal of fun. A gene is a section of DNA that can be copied into RNA (which may then provide the instructions for making a protein), and each gene has been given a name. Some names are boring – such as leucine-rich repeat kinase 2 (or LRRK2… Boring!) – while other names are rather amusing.
For example, there is one fly gene called indy, which stands for I‘m Not Dead Yet. Flies with genetic variation in this gene have longer than average lifespans (Click here to read more about this).
Another amusingly named gene is Cheap Date. Flies with a genetic mutation in this gene are very susceptible to alcohol (Click here to read more about this).
There is also Ken and Barbie – genetic variations in this gene result in a lack of external genitalia (Click here to read more about this). There are lots of great gene names: “lunatic fringe”, “headcase” and “mothers against decapentaplegia (MAD)”. Like I said, fly genetists have a lot of fun.
But one of the most popular gene names in all of biology is a gene called Sonic Hedgehog.
What is Sonic Hedghog?
As the amazing Australian Parkinson’s Mission project prepares to kick off, across the creek in my home land of New Zealand, another very interesting clinical trial programme for Parkinson’s is also getting started. The study is being conductetd by a US biotech firm called resTORbio Inc.
The drug being tested in the study is called RTB101.
It is an orally-administered TORC1 inhibitor, and it represents a new class of drug in the battle against Parkinson’s.
In today’s post, we will look at what TORC1 is, how the drug works, the preclinical research supporting the trial, and what this new clinical trial will involve.
Rapa Nui. Source: Chile.Travel
Today’s post kicks off on an amazing south Pacific island… which is not New Zealand.
In 1965, a rather remarkable story began in one of the most remote inhabited places on Earth – the mysterious island of Rapa Nui (or “Easter Island”).
And when we say ‘remote’, we really do mean remote. Did you know, the nearest inhabited island to Rapa Nui is Pitcairn Island, which is 2,075 kilometres (1,289 mi) away. And Santiago (the capital of Chile) is 2,500 miles away – that’s a four-hour+ flight!!!
Rapa Nui is the very definition of remote. It is as remote as remote gets!
Does Amazon deliver to the town of Hanga Roa? Source: Atlasandboots
Anyways, in 1965 a group of researchers arrived at Rapa Nui with the goal of studying the local inhabitants. They wanted to investigate their heredity, environment, and the common diseases that affected them, before the Chilean government built a new airport which would open the island up to the outside world.
It was during this investigation, that one of the researchers – a University of Montreal microbiologist named Georges Nógrády – noticed something rather odd.
At the time of the study, wild horses on Rapa Nui outnumbered humans (and stone statues).
Wild horses roaming the east coast of Rapa Nui. Source: Farflungtravels
But what was odd about that?
Georges discovered that locals had a very low frequency of tetanus – a bacterial infection of the feet often found in places with horses. He found this low incidence of tetanus particularly strange given that the locals spent most of their time wandering around the island barefoot. So Georges decided to divide the island into 67 regions and he took a soil sample from each for analysis.
In all of the vials collected, Nógrády found tetanus spores in just one vial.
Something in the soil on Rapa Nui was extremely anti-fungal.
In 1969, Georges’ collection of soil samples was given to researchers from the pharmaceutical company Wyeth and they went looking for the source of the anti-fungal activity. After several years of hard work, the scientists found a soil bacteria called Streptomyces hygroscopicus which secreted a compound that was named Rapamycin – after the name of the island – and they published this report in 1975:
Title: Rapamycin (AY-22, 989), a new antibiotic
Authors: Vézina C, Kudelski A, Sehgal SN.
Journal: J Antibiot (Tokyo). 1975 Oct;28(10):721-6.
PMID: 1102508 (This report is OPEN ACCESS if you would like to read it)
It is no understatement to say that this was a major moment in biomedical history. So much so that there is actually a plaque on the island commemorating the discovery of rapamycin:
Why was the discovery of ‘anti-fungal’ rapamycin so important?!?
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?
On the 26-31st March, the 14th International Conference on Alzheimer’s and Parkinson’s Diseases (or ADPD meeting) was held in Lisbon, Portugal.
For 5 days – between 8:30am and 7:30pm each day – over 4000 researchers were able to attend lectures of new results and ideas, in any of 8 different auditoriums. Alternatively, they could wander among hundreds of research posters.
It was a marathon effort, however, for all attendees. And a great deal of new results were shared.
In today’s post, we will discussed what was presented at the 2019 ADPD meeting and what was actually learnt.
Lisbon. Source: stmed
Lisbon is a city, midway down the western coast of the Iberian Peninsula.
It is home to a little over 500,000 people (3 million in the wider metropolitan area), and it serves as the capital city for the Portuguese people.
The Castelo de Sao Jorge, rises above Lisbon. Source: Wikipedia
Interestingly, it is the 2nd oldest European capital city (after Athens), and has had a rich and fascinating history given its strategic location. But on the 1st November 1755, 20% of the population were killed and 85% of the city’s structures were destroyed by a terrible earthquake and subsequent tsunami, which resulted in the vast majority of the city being rebuilt.
The ‘new city’ is laid out in bairros de Lisboa (neighbourhoods of Lisbon) across a hilly landscape, providing views of the River Tagus at every vantage point. And while walking the steep cobblestoned streets is delightful, there is a system of vintage public trams that can take a lot of the leg work out of the effort.
During the last week of March 2019, Lisbon was the site of the ADPD meeting.
What is the ADPD meeting?
At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during March 2019.
The post is divided into seven parts based on the type of research:
So, what happened during March 2019?
In world news:
2nd March – SpaceX successfully launch their Crew Dragon rocket on it’s first un-manned mission into space. One day later it docked with the international space station.
5th March – A second case of sustained remission from HIV was reported. This news comes ten years after the original “Berlin Patient” (Click here to read more about this).
15th March – Cyclone Idai made landfall on Mozambique, causing loss of life, mass flooding, and power outages in south-eastern Africa.
25-26th March – the International Parkinson Disease Genomics Consortium met in Lisbon (Portugal) for their annual meeting. 100+ genetics experts from around the world gathered to discuss all of their new research on the genetics of Parkinson’s – it was an amazing meeting (Click here to read a SoPD post on this meeting).
26-31st March – the 14th International Conference on Alzheimer’s & Parkinson’s Disease was held in Lisbon (Portugal). 4000 researchers from around the world invaded the city for five days of lectures & presentations. The results of many clinical trials were presented and exciting new data was discussed (a SoPD post is in the works on this meeting).
In the world of Parkinson’s research, a great deal of new research and news was reported:
In March 2019, there were 869 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (2429 for all of 2019 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 6 pieces of Parkinson’s news
If you just ‘read the label on the can’ you would be mistaken in thinking that the International Parkinson Disease Genomics Consortium (IPDGC) is just an international group of researchers who are interested in the genetics of Parkinson’s.
The group is so much more than that!
I was recently invited to attend their annual meeting in Lisbon (Portugal) and it was a revelation.
In today’s post, we will discuss the group, review some of the research it has produced, and I’ll explain why I am so impressed with this organisation.
You will often hear researchers complaining about the state of science in the modern world. Go to any conference and they will express their concerns about the lack of funding, the lack of job security, the pressure from institutes to publish in the best journals, and the stress their jobs put on their lives (families, etc).
A career in scientific research is a privilege bestowed by society (and that should never be forgiven), but it comes with some brutal realities. It is not a 9-5 job. It is an unrelenting, all consuming beast. An abusive (failure and rejection are the norm) obsession that one cannot seem to recover from.
It’s really, really hard (I have seen marriages dissolve and lives basically ruined by it).
There is, however, a lot of discussion at research gatherings (and online) about how we can improve the ‘broken model of research’, and in today’s post I would like to share with you one group that is a shining, proactive example of such efforts.
I was invited to attend the annual meeting of the IPDGC.
And I’m really glad that I went.
What is the IPDGC?