Tagged: genetic

Non-invasive gene therapy: “You never monkey with the truth”

Gene therapy involves treating medical conditions at the level of DNA – that is, altering or enhancing the genetic code inside cells to provide therapeutic benefits rather than simply administering drugs. Usually this approach utilises specially engineered viruses to deliver the new DNA to particular cells in the body.

For Parkinson’s, gene therapy techniques have all involved direct injections of these engineered viruses into the brain – a procedure that requires brain surgery. This year, however, we have seen the EXTREMELY rapid development of a non-invasive approach to gene therapy for neurological condition, which could ultimately see viruses being injected in the arm and then travelling up to the brain where they will infect just the desired population of cells.

Last week, however, this approach hit a rather significant obstacle.

In today’s post, we will have a look at this gene therapy technology and review the new research that may slow down efforts to use this approach to help to cure Parkinson’s.


Gene therapy. Source: rdmag

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 begun to see more and more 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.

A good 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.

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Levodopa. Source: Drugs

This pill form of treating a disease is only a temporary solution though. People with Parkinson’s – 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?

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The TAU of Parkinson’s

Here at the SoPD, we regularly talk about the ‘bad boy’ of Parkinson’s disease – a protein called Alpha Synuclein.

Twenty years ago this year, genetic variations were identified in the alpha synuclein gene that increase one’s risk of developing Parkinson’s. In addition, alpha synuclein protein was found to be present in the Lewy bodies that are found in the brains of people with Parkinson’s. Subsequently, alpha synuclein has been widely considered to be the villain in this neurodegenerative condition and it has received a lot of attention from the Parkinson’s research community.

But it is not the only protein that may be playing a role in Parkinson’s.

Today’s post is all about TAU.


Source: Wallpaperswide

I recently informed my wife that I was thinking of converting to Taoism.

She met this declaration with more of a smile than a look of shock. And I was expecting the latter, as shifting from apatheism to any form of religious belief is a bit of a leap you will appreciate.

When asked to explain myself, I suggested to her that I wanted to explore the mindfulness of what was being proposed by Lao Tzu (the supposed author of the Tao Te Ching – the founding document of Taoism).

This answer also drew a smile from her (no doubt she was thinking that Simon has done a bit of homework to make himself sound like he knows what he was talking about).

But I am genuinely curious about Taoism.

Most religions teach a philosophy and dogma which in effect defines a person. Taoism – which dates from the 4th century BCE – flips this concept on its head. It starts by teaching a single idea: The Tao (or “the way”) is indefinable. And then it follows up by suggesting that each person should discover the Tao on their own terms. Given that most people would prefer more concrete definitions in their own lives, I can appreciate that a lot of folks won’t go in for this approach.

Personally speaking, I quite like the idea that the Tao is the only principle and everything else is a just manifestation of it.

According to Taoism, salvation comes from just one source: Following the Tao.

Source: Wikipedia

Oh and don’t worry, I’m not going to force any more philosophical mumbo jumbo on you – Taoism is just an idea I am exploring as part of a terribly clichéd middle-life crisis I’m working my way through (my wife’s actual response to all of this was “why can’t you just be normal and go buy a motor bike or something?”).

My reason for sharing this, however, is that this introduction provides a convenient segway to what we are actually going to talk about in this post.

You see, some Parkinson’s researchers are thinking that salvation from neurodegenerative conditions like Parkinson’s will come from just one source: Following the TAU.

What is TAU?

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The LRRK Ascending

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.

sergey_brin

Nice guy.

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.

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CRISPR-Cas9: “New CRISPY Parkinson’s research”

Recently a Parkinson’s-associated research report was published that was the first of many to come.

It involves the use of a genetic screening experiment that incorporates new technology called ‘CRISPR’.

There is an absolute tidal wave of CRISPR-related Parkinson’s disease research coming down the pipe towards us, and it is important that the Parkinson’s community understands how this powerful technology works.

In today’s post we will look at what the CRISPR technology is, how it works, what the new research report actually reported, and discuss how this technology can be used to tackle a condition like Parkinson’s.


Me and my mother (and yes, the image is to scale). Source: Openclipart

My mother: Simon, what is all this new ‘crispy’ research for Parkinson’s I heard about on the news?

Me: Huh? (I was not really paying attention to the question. Terrible to ignore one’s mother I know, but what can I say – I am the black sheep of the family)

My mother: Yes, something about ‘crispy’ and Parkinson’s.

Me: Oh! You mean CRISPR. Yeah, it’s really cool stuff.

My mother: Ok, well, can you explain it all to me please, this ‘Crisper’ stuff?

Me: Absolutely.

CRISPR.101 (or CRISPR for beginners)

In almost every cell of your body, there is a nucleus.

It is the command centre for the cell – issuing orders and receiving information concerning everything going on inside and around the cell. The nucleus is also a storage bank for the genetic blueprint that provides most of the instructions for making a physical copy of you. Those grand plans are kept bundled up in 23 pairs of chromosomes, which are densely coiled strings of a molecule called Deoxyribonucleic acid (or DNA).

DNA’s place inside the cell. Source: Kids.Britannica

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Trying to ‘beet’ Parkinson’s in the developing world

Recently I discussed my ‘Plan B’ idea, which involves providing a cheap alternative to expensive drugs for folks living in the developing world with Parkinson’s (Click here for that post).

While doing some research for that particular post, I came across another really interesting bit of science that is being funded by Parkinson’s UK.

It involves Beetroot.

In today’s post we will look at how scientists are attempting turn this red root vegetable into a white root vegetable in an effort to solve Parkinson’s in the developing world.


Pompeii and Mount Vesuvius. Source: NationalGeo

During visits to the ancient Roman city of Pompeii (in Italy), tourists are often drawn by their innocent curiosity to the ‘red light’ district of the city. And while they are there, they are usually amused by the ‘descriptive’ murals that still line the walls of the buildings in that quarter.

So amused in fact that they often miss the beetroots.

Huh? Beetroots?

Yes, beetroots.

I’m not suggesting that anyone spends a great deal of time making a close inspection of the walls, but if you look very carefully, you will often see renditions of beetroots.

They are everywhere. For example:

Two beetroots hanging from the ceiling.

Again: Huh?

The Romans considered beetroot to be quite the aphrodisiac, believing that the juice ‘promoted amorous feelings’. They also ate the red roots for medicinal purposes, consuming it as a laxative or to cure fever.

And this medicinal angle lets me segway nicely into the actual topic of today’s post. You see, in the modern era researcher are hoping to use beetroot for medicinal purposes again. But this time, the beetroot will be used to solve an issue close to my heart: treating people with Parkinson’s in the developing world.

Using beetroot to treat Parkinson’s?

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NIX-ing the PARKIN and PINK1 problem

In American slang, to ‘nix‘ something is to ‘put an end to it’.

Curiously, a protein called NIX may be about to help us put an end to Parkinson’s disease, at least in people with specific genetic mutations.

In today’s post we will look at what NIX is, outline a new discovery about it, and discuss what this new information will mean for people living with Parkinson’s disease.


Sydney harbour. Source: uk.Sydney

Before we start, I would like the reader to appreciate that I am putting trans-Tasman rivalry side here to acknowledge some really interesting research that is being conducted in Australia at the moment.

And this is really interesting.

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

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 – the waste disposal system of each cell).

What does this have to do with Parkinson’s disease?

Well, about 10% of Parkinson’s cases are associated with particular genetic variations that render people vulnerable to developing the condition. Some of these mutations are in sections of DNA (called genes) that provide the instructions for proteins that are involved in the process of mitophagy. Two genes, in particular, are the focus of a lot of Parkinson’s-related research – they are called PARKIN and PINK1.

What do PARKIN and PINK1 do?

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We need a clinical trial of broccoli. Seriously!

In a recent post, I discussed research looking at foods that can influence the progression of Parkinson’s (see that post here). I am regularly asked about the topic of food and will endeavour to highlight more research along this line in future post.

In accordance with that statement, today we are going to discuss Cruciferous vegetables, and why we need a clinical trial of broccoli.

I’m not kidding.

There is growing research that a key component of broccoli and other cruciferous vegetables – called Glucoraphanin – could have beneficial effects on Parkinson’s disease. In today’s post, we will discuss what Glucoraphanin is, look at the research that has been conducted and consider why a clinical trial of broccoli would be a good thing for Parkinson’s disease.


 

Cruciferous vegetables. Source: Diagnosisdiet

Like most kids, when I was young I hated broccoli.

Man, I hated it. With such a passion!

Usually they were boiled or steamed to the point at which they have little or no nutritional value, and they largely became mush upon contact with my fork.

The stuff of my childhood nightmares. Source: Modernpaleo

As I have matured (my wife might debate that statement), my opinion has changed and I have come to appreciate broccoli. Our relationship has definitely improved.

In fact, I have developed a deep appreciation for all cruciferous vegetables.

And yeah, I know what you are going to ask:

What are cruciferous vegetables?

Cruciferous vegetables are vegetables of the Brassicaceae family (also called Cruciferae). They are a family of flowering plants commonly known as the mustards, the crucifers, or simply the cabbage family. They include cauliflower, cabbage, garden cress, bok choy, broccoli, brussels sprouts and similar green leaf vegetables.

Cruciferous vegetables. Source: Thetherapyshare

So what have Cruciferous vegetables got to do with Parkinson’s?

Well, it’s not the vegetables as such that are important. Rather, it is a particular chemical that this family of plants share – called Glucoraphanin – that is key.

What is Glucoraphanin?

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O’mice an’ men – gang aft agley

This week a group of scientists have published an article which indicates differences between mice and human beings, calling into question the use of these mice in Parkinson’s disease research.

The results could explain way mice do not get Parkinson’s disease, and they may also partly explain why humans do.

In today’s post we will outline the new research, discuss the results, and look at whether Levodopa treatment may (or may not) be a problem.


The humble lab mouse. Source: PBS

Much of our understanding of modern biology is derived from the “lower organisms”.

From yeast to snails (there is a post coming shortly on a snail model of Parkinson’s disease – I kid you not) and from flies to mice, a great deal of what we know about basic biology comes from experimentation on these creatures. So much in fact that many of our current ideas about neurodegenerative diseases result from modelling those conditions in these creatures.

Now say what you like about the ethics and morality of this approach, these organisms have been useful until now. And I say ‘until now’ because an interesting research report was released this week which may call into question much of the knowledge we have from the modelling of Parkinson’s disease is these creatures.

You see, here’s the thing: Flies don’t naturally develop Parkinson’s disease.

Nor do mice. Or snails.

Or yeast for that matter.

So we are forcing a very un-natural state upon the biology of these creatures and then studying the response/effect. Which could be giving us strange results that don’t necessarily apply to human beings. And this may explain our long history of failed clinical trials.

We work with the best tools we have, but it those tools are flawed…

What did the new research report find?

This is the study:


Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D
Journal: Science, 07 Sept 2017 – Early online publication
PMID: 28882997

The researchers who conducted this study began by growing dopamine neurons – a type of cell badly affected by Parkinson’s disease – from induced pluripotent stem (IPS) cells.

What are induced pluripotent stem cells?

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Hey DJ, I-so-sit-rate!

The title of this post probably reads like the mad, drug-fuelled scream of a drunk Saturday night party animal, but the elements of it may be VERY important for a particular kind of Parkinson’s disease.

Mutations in a gene called DJ-1 can cause an early onset form of Parkinson’s disease. The protein of DJ-1 plays an important role in how cells handle oxidative stress – or the increase in damaging free radicals (explained below).

This week researchers announced that they have found an interesting new therapeutic target for people with DJ-1 associated Parkinson’s disease: A chemical called Isocitrate.

In this post, we will discuss what DJ-1 is involved with Parkinson’s disease, how isocitrate helps the situation, and what the results of new research mean for future therapeutic strategies.


original-26772-1364707371-8

Source: Listchallenge

In 2017, we are not only observing the 200 year anniversary of the first description of Parkinson’s disease (by one Mr James Parkinson), but also the 20th anniversary of the discovery of the first genetic variation associated with the condition (Click here to read more about that). Our understanding of the genetics of Parkinson’s disease since 1997, has revolutionised the way we look at Parkinson’s disease and opened new doors that have aided us in our understanding.

During the last 20 years, we have identified numerous sections of DNA (these regions are called genes) where small errors in the genetic coding (mutations or variants) can result in an increased risk of developing Parkinson’s disease. As the graph below indicates, mutations in some of these genes are very rare, but infer a very high risk, while others are quite common but have a low risk of Parkinson’s disease.

The genetics of PD. Source: Journal of Parkinson’s disease

Some of the genetic mutation need to be provided by both the parents for Parkinson’s to develop (an ‘autosomal recessive‘ mutation – the yellow circles in the graph above); while in other cases the genetic variant needs only to be provided by one of the parents (an ‘autosomal dominant’ mutation – the blue circles). Many of the genetic mutations are very common and simply considered a region of increased risk (green circles).

Importantly, all of these genes provide the instructions for making a protein – which are the functional parts in a cell. And each of these proteins have specific roles in biological processes. These functions tell us a little bit about how Parkinson’s disease may be working. Each of them is a piece of the jigsaw puzzle that we are trying to finish. As you can see in the image below, many of the genes mentioned in the graph above give rise to proteins that are involved in different parts of the process of autophagy – or the waste disposal system of the cell. You may notice that some proteins, like SCNA (otherwise known as alpha synuclein), are involved in multiple steps in this process.

The process of autophagy. Source: Nature

In today’s post we are going to look at new research regarding just one of these genes/proteins. It is called DJ-1, also known as Parkinson disease protein 7 (or PARK7).

What is DJ-1?

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The next killer APP: LRRK2 inhibitors?

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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

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:

PDAD

Title: Parkinson’s disease in patients with Alzheimer’s disease.
Authors: Leverenz J, Sumi SM.
Journal: Arch Neurol. 1986 Jul;43(7):662-4.
PMID: 3729742

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).

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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???

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