Category: Uncategorized

When undruggable becomes druggable

 

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.

 


Source: PPcorn

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.
PMID: 9092472

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?

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The 2019 ADPD meeting

 

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.

Source: Portugaltravelguide

During the last week of March 2019, Lisbon was the site of the ADPD meeting.

What is the ADPD meeting?

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Monthly Research Review – March 2019

 

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:

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials
  • Clinical trial news
  • Other news
  • Review articles/videos

 


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

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IPDGC: The genetics of Parkinson’s

 

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.

 


Source: Nothinginbiology

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?

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Deep Mitochondrial stimulation?

 

 

Recently some researchers conducted an analysis of some postmortem brains from people with Parkinson’s and they discovered something rather curious.

Half of the brains that they analysed came from people with Parkinson’s who had been given deep brain stimulation (or DBS) to help manage their symptoms. When the researchers analysed the mitochondria – the powerstations of each cell – in the dopamine neurons of these brain, they found that the DBS treatment had helped to improve the number of mitochondria in these cells.

Specifically, the DBS treatment “seemed to have inhibited or reversed the reduction in mitochondrial volume and numbers” that was observed in the Parkinson’s brains that had not had DBS.

In today’s post, we will look at what DBS is, what the new research report found, and what these new findings could mean for the Parkinson’s community.

 


The worst thing. Source: Greatist

Do you know the worst thing that happens to us in life?

We wake up each day.

Every day of our lives (so far) we have woken up and been given – without any kind of justification – another 16 or so hours to do whatever we want with.

Regardless of one’s physical/mental state, this is a bad thing.

This continuous pattern is what is referred to in psychology as a ‘continuous schedule of reinforcement’. Such regimes instill complacency and – worse – expectation. They quickly lead to people taking things for granted. All of us are guilty of thinking “I’ll do it tomorrow”.

Source: Taskcracker

Such a continuous pattern of reinforcement does not prepare one well for a life in scientific research, where there isn’t a constant schedule of reinforcement (quite the opposite actually). Experiments regularly go wrong (reagents/equipment fail), grants/manuscripts get rejected – it can be rather brutal.

But here is where the addictive component of science comes into effect. Every so often, something works. And even better, every so often something unexpected happens – an ‘intermittent/irregular schedule of reinforcement’. An experiment will occasionally spit out a completely unexpected result, which could change everything.

Source: Granger

These are the moments of insights that researchers are slaving for. The instant that they are the first to “walk on the moon”.

They are moments to savour.

And this must have been the state of mind for some researchers who dicovered something surprising and absolutely remarkable recently while they were looking at some postmortem brains from individuals with Parkinson’s who had been treated with deep brain stimulation.

What is deep brain stimulation?

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AdoCbl + LRRK2 = modulation

 

Approximately 1 person with Parkinson’s in every 100 will have a genetic variation in a specific section of their DNA that is referred to as LRRK2 – pronounced ‘lark 2’. The variation results in changes to the activity of the LRRK2 protein, and these changes are suspected of influencing the course of LRRK2-associated Parkinson’s.

Numerous biotech companies are now developing LRRK2 targetting agents that will modulate the activity of the LRRK2 protein.

Recently, however, a research report was published which points towards a potentially accessible method of LRRK2 modulation – one of the active forms of vitamin B12 – and if this research can be independently replicated, it may provide certain members of the Parkinson’s community with another means of dealing with the condition.

In today’s post, we will look at what LRRK2 is, review the new research, and discuss what could happen next.

 


This is Sergey Brin.

You may have heard of him – he was one of the founders of a small company called “Google”. Apparently it does something internet related.

Having made his fortune changing the way we find stuff, he is now turning his attention to other projects.

One of those other projects is close to our hearts: Parkinson’s.

Why is he interested in Parkinson’s?

In 1996, Sergey’s mother started experiencing numbness in her hands. Initially it was believed to be a bit of RSI (Repetitive strain injury). But then her left leg started to drag. In 1999, following a series of tests and clinical assessments, Sergey’s mother was diagnosed with Parkinson’s.

The Brin Family – Sergey and his mother on the right. Source: CS

It was not the first time the family had been affected by the condition – Sergey’s late aunt had also had Parkinson’s.

Given this coincidental family history of this particular condition, both Sergey and his mother decided to have their DNA scanned for any genetic errors (also called ‘variants’ or ‘mutations’) that are associated with an increased risk of developing Parkinson’s. And they discovered that they were both carrying a genetic variation in a gene (a section of DNA that provides the instructions for making a protein) called PARK8 – one of the Parkinson’s-associated genes (Click here to read more about the genetics of Parkinson’s and the PARK genes).

The PARK8 gene is also known as Leucine-rich repeat kinase 2 (or LRRK2 – pronounced ‘lark 2’).

What is LRRK2?

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The Joy of discovery: On the smell of Parkinson’s

 

Today saw the publication of one of my favourite stories of Parkinson’s research.

It is a tale of courage, serendipity, hard work, and (most importantly) an idea for a research project that came from the Parkinson’s community, but has now opened new doors for researchers and could have important implications for everyone.

In 2012, former nurse Joy Milne was attending a Parkinson’s support group meeting in Edinburgh (Scotland) when she bravely asked the scientist presenting research that day, “Do people with Parkinson’s smell different?

What happened next is likely to become that stuff of legend.

In today’s post, we will discuss the back story, review a new research report investigating the smell of Parkinson’s, and consider what the results could mean for the Parkinson’s community.

 


Erasto Mpemba & Denis Osborne. Source: Rekordata

In 1963, Dr. Denis G. Osborne – from the University College in Dar es Salaam – was invited to give a lecture on physics to the students at Magamba Secondary School (Tanganyika, Tanzania). At the end of his lecture, a 13 year old student, named Erasto Mpemba, stood up and asked Dr Osbrone:

If you take two similar containers with equal volumes of water, one at 35 °C (95 °F) and the other at 100 °C (212 °F), and put them into a freezer, the one that started at 100 °C (212 °F) freezes first. Why?”

The question was met by ridicule from his fellow classmates.

But to his credit, Dr Osborne went back to his lab and conducted some experiments based on the question, confirming Mpemba’s observation. Together they published the results in 1969, and the phenomenon (the process in which hot water can freeze faster than cold water) is now referred to as the Mpemba effect.

Mpemba effect. Source: Wikipedia

The point is: All scientific discoveries start with an observation, followed by an experiment.

And scientists do not have a monopoly on this.

There have been many cases of ‘laypeople’ – like Erasto Mpemba – making important observations. And recently the Parkinson’s world had a perfect example of this. It’s very own Erasto Mpemba moment.

What are you talking about?

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Neu-Ro-Mela-Nin

 

Recently a really interesting research report was published that presented several rather amazing findings.

The researchers forced dopamine-producing cells in a rodent brain to start making a protein called neuromelanin and by doing this, they witnessed the occurence of Parkinson’s-like features (motor issues, Lewy body-like structures, and cell death).

The report also suggested a method by which this outcome could be reduced or rescued.

But the amazing part is that neuromelanin was previously considered to be protective and this new finding suggests we may need to rethink that idea.

In today’s post, we will discuss what neuromelanin is, what this new report found, and how this new knowledge could be useful in the context of Parkinson’s.

 


heiko-braak-01Prof Heiko Braak. Source – Memim.com

This is Prof Heiko Braak.

Many years ago, he sat down and examined hundreds of postmortem brains from people with Parkinson’s.

He had collected brains from people who passed away at different stages of the condition, and was looking for any kind of pattern that might explain where and how the disease starts. His research led to what is referred to as the “Braak staging” model of Parkinson’s – a six step explanation of how the condition spreads up from the brain stem (the top of the spinal cord) and into the rest of the brain (Click here and here to read more about this).

nrneurol.2012.80-f1The Braak stages of PD. Source: Nature

Braak found that certain populations of cells in the brain were more vulnerable to Parkinson’s than others, such as the dopamine neurons in a region called the substantia nigra, the noradrenergic neurons of the locus coeruleus, and the neurons of the dorsal motor nucleus of the vagus (don’t worry about what any of those names actually mean, I’m just trying to sound smart and make you think that I know what I’m taking about).

One feature that all of these populations of neurons all share in common – in addition to vulnerability to Parkinson’s – is the production of pigment called neuromelanin.

What is neuromelanin?

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The Eve of Parkinson’s

Approximately 40% of the people affected by Parkinson’s are female. This number can vary across regions, but women still make up a large portion of the affected community.

That said, there is unfortunately very little research investigating women’s issues in Parkinson’s.

There are now efforts to correct this situation, however, and this change is being brought about by members of the affected community.

In today’s post, we will discuss some of what is known about how Parkinson’s affects women differently.

 


Source: Electricrunway

Why is today – the 8th March – called International women’s day? (backdated due to @#%$£&* technical issues!).

I don’t actually know. Perhaps because it’s politically correct that everyone should get their own day/month now?

Nice try.

The United Nations began celebrating International Women’s Day on the 8th March in 1975. But observation of the day date back to the early years of that century, and although the suffrage movement was occurring at the same time, International women’s day was very much a socialist idea.

And this shows itself in the timeline of events. For example, International Women’s Day was first observed on the 19th March, 1911 in Germany thanks to socialist activists like Luise Zietz, Käte Duncker and Clara Zetkin. But it wasn’t until 1918 that women were actually given the right to vote.

And remarkably, it was not until 1977 that the United Nations General Assembly invited its member states to proclaim the 8th March as the “UN Day for women’s rights and world peace”.

Source: IWD

Interesting. But what does this have to do with Parkinson’s?

There is an imbalance in the amount of research being conducted on women in Parkinson’s.

In particular, there is a poverty of information regarding aspects of daily life for women living with Parkinson’s, especially those with young onset Parkinson’s.

What do you mean?

If you go to the medical research search engine Pubmed, and type in Parkinson’s and menopause, there are only 107 publications (dating back to 1971, 41 of them since 2010). To put that in context, there are over 105,000 research reports on Parkinson’s on the pubmed database. And most of them are not about menopause research, they simply mention the word menopause in their text. Similarly there are only 25 reports on parkinson’s and menstruation (and only 6 of them have been conducted since 2000!?!?).

Searching for male associated key words such as parkinson’s and prostate yeilds 177 publications (104 of which have been published since 2010 only).

And searching for Parkinson’s and male results in 43,000 reports, but searching for Parkinson’s and female only gives 36,000 reports.

So why the disparity?

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We need to talk about the UPDRS

 

“The measure of who we are is what we do with what we have” – Vince Lombardi

The measuring of Parkinson’s is complicated. There is such enormous variability between individual cases that the task of assessing people is very difficult.

The primary method that is used in clinics around the world is the Unified Parkinson’s Disease Rating Scale (or UPDRS). It is by no means perfect, and recently (in the wake of several unsuccessful clinical trials) there has been heated debate as to whether it is really up to the task.

Does it accurately reflect the condition? Does it really capture the lived experience? Can it pick up subtle changes associated with potentially disease modifying therapies in clinical trials? Or is it simply a “we’ve always done it this way” kind of tool?

In today’s post, we will look at what the UPDRS is, discuss some of the criticisms associated with it, and consider what solutions to those issues could look like.

 


Source: Wired

This is Andy Grove and his story is rather remarkable.

Born in 1936 to a Jewish family in Budapest, he managed to survive the Nazis, and then fleed Hungary when Soviet tanks started rolling in. Arriving in the US with absolutely nothing, he taught himself English, before going to City College of New York and later the University of California (Berkeley) where he received a PhD in chemical engineering.

And that was just the start of his amazing tale.

After completing his PhD (and publishing a textbook on semiconductors), Grove joined the seminal Silicon Valley company – Fairchild Semiconductor – in 1963. He worked his way up from researcher to assistant director of development, before becoming the first person that Robert Noyce and Gordon Moore (of Moore’s Law fame) hired after they departed Fairchild to start their own little company in 1968.

The name of that company was Intel.

Source: Wikipedia

Grove also worked his way up the ladder at Intel – from director of engineering to CEO – and he is credited with transforming the company from a struggling memory chip maker into the processor powerhouse it is today. He was Time’s ‘Man of the Year’ in 1997 and he was a widely revered figure in Silicon valley.

Source: Time

But the path to success was not easy.

Having survived prostate cancer in 1995, Grove was diagnosed with Parkinson’s in 2000. Viewing the situation as a problem solving exercise, he poured tens of millions of his own money into researching Parkinson’s.

Andy & Michael J Fox. Source: MJFF

But coming from the world of ‘Moore’s Law’, Grove became frustrated by a.) the slow speed of progress in the world of biomedical research and b.) the tools used to assess it.

In particular, he disliked the UPDRS, which he referred to as a “piece of crap” (Source – you should read the linked article).

What is the UPDRS?

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