Tagged: autophagy

Mickey becomes more human?

For a long time researchers have lacked truly disease-relevant models of Parkinson’s.

We have loaded cells with toxins to cause cell death, we have loaded cells with mutant proteins to cause cell death, we have loaded cells with… well, you get the idea. Long story short though, we have never had proper models of Parkinson’s – that is a model which present all of the cardinal features of the condition (Lewy bodies, cell loss, and motor impairment).

The various models we have available have provided us with a wealth of knowledge about the biology of how cells die and how we can protect them, which has led to numerous experimental drugs being tested in the clinic. But there has always been a linger question of ‘how disease-relevant are these models?’

This situation may be about to change.

In today’s post we will look at new research in which Japanese researchers have genetically engineered mice in which they observed the generation of Lewy bodies, the loss of dopamine neurons and motor impairments. We will look at how these mice have been generated, and what it may tell us about Parkinson’s.


Walt Disney. Source: PBS

Ok, before we start today’s post: Five interesting facts about the animator Walt Disney (1901 – 1966):

  • Disney dropped out of high school at age 16 with the goal of joining the Army to help out in the war effort. He was rejected for being underage, but was able to get a job as an ambulance driver with the Red Cross in France.
  • From 1928 (the birth of Mickey Mouse) until 1947, Disney himself performed the voice of Mickey.
  • Mickey Mouse was originally named “Mortimer Mouse”, but it was Disney’s wife who suggested that the name Mortimer sounded too pompous (seriously, can you imagine a world with the “Mortimer Mouse show”?). She convinced Disney to change the name to Mickey (the name Mortimer was later given to one of Mickey’s rivals).
  • To this day, Disney holds the record for the most individual Academy Awards and nominations. Between 1932 and 1969, he won 22 Academy Awards and was nominated 59 times (Source).
  • And best of all: On his deathbed as he lay dying from lung cancer, Disney wrote the name “Kurt Russell” on a piece of paper. They were in effect his ‘last words’. But no one knows what they mean. Even Kurt is a bit perplexed by it all. He (along with many others) was a child actor contracted to the Disney company at the time, but why did Walt write Russell’s name as opposed to something more deep and meaningful (no disrespect intended towards Mr Russell).

Actor Kurt Russell. Source: Fxguide

When asked why he thought his great creation “Mickey mouse” was so popular, Walt Disney responded that “When people laugh at Mickey Mouse, it’s because he’s so human; and that is the secret of his popularity”.

Mickey Mouse. Source: Ohmy.Disney

This is a curious statement.

Curious because in biomedical research, mice are used in experiments to better understand the molecular pathways underlying basic biology and for the testing of novel therapeutics, and yet they are so NOT human.

There are major biological differences between us and them.

Not human. Source: USNews

It has been a major dilemma for the research community for some time with regards to translating novel therapies to humans, and it raises obvious ethical questions of whether we should be using mice at all for the basic research if they are so different from us. This problem is particularly apparent in the field of immunology, where the differences between ‘mice and men’ is so vast in some cases that researcher have called for moving away from mice entirely and focusing on solely human models (Click here and here for a good reads on this topic).

What does this have to do with Parkinson’s?

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FASN-ating PINK research

Pink

In 2018, there is one particular clinical trial that I will be watching, because the drug being tested could have a big impact on certain kinds of Parkinson’s.

The clinical trial is focused on people with cancer and they will be treated with a drug called TVB-2640TVB-2640 is an inhibitor of an enzyme called fatty acid synthase (or FAS). 

In today’s post we will discuss why TVB-2640 might be a useful treatment for certain kinds of Parkinson’s.


Mitochondria

Mitochondria and their location in the cell. Source: NCBI

 

Regular readers of this blog are probably getting sick of the picture above.

I use it regularly on this website, because a.) it nicely displays a basic schematic of a mitochondrion (singular), and where mitochondria (plural) reside inside a cell. And b.) a lot of evidence is pointing towards mitochondrial dysfunction in Parkinson’s.

What are mitochondria?

Mitochondria are the power stations of each cell. They help to keep the lights on. Without them, the party is over and the cell dies.

How do they supply the cell with energy?

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.

Source: Mangomannutrition

What does this have to do with Parkinson’s?

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Novartis focuses on improving PARKIN control

Last week, as everyone was preparing for Christmas celebrations, researchers at the pharmaceutic company Novartis published new research on a gene that is involved with Parkinson’s, called PARKIN (or PARK2).

They used a new gene editing technology – called CRISPR – to conduct a large screening study to identify proteins that are involved with the activation of PARKIN.

In today’s post we will look at what PARKIN does, review the research report, and discuss how these results could be very beneficial for the Parkinson’s community.


Source: Novartis

As many people within the Parkinson’s community will be aware, 2017 represented the 200th anniversary of the first report of Parkinson’s disease by James Parkinson.

It also the 20th anniversary of the discovery of first genetic mutation (or variant) that increases the risk of developing Parkinson’s. That genetic variation occurs in a region of DNA (a gene) called ‘alpha synuclein’. Yes, that same alpha synuclein that seems to play such a critical role in Parkinson’s (Click here to read more about the 20th anniversary).

In 2018, we will be observing the 20th anniversary of the second genetic variation associated with Parkinson.

That gene is called PARKIN:

Title: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.
Authors: Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N
Journal: Nature. 1998 Apr 9; 392(6676):605-8
PMID: 9560156

In 1998, Japanese researchers published this report based on 5 individuals from 4 Japanese families who were affected by juvenile-onset Parkinson’s. In family 1, the affected individual was a female, 43 years old, born of first-cousin parents, and her two younger brothers are healthy. Her condition was diagnosed in her teens and it had then progressed very slowly afterwards. Her response to L-dopa was very positive, but L-dopa-induced dyskinesia were frequent. In family 2-4, affected individuals (born to unrelated parents) exhibited very similar clinical features to the subject in family 1. The age of onset was between 18 to 27 years of age.

Using previous research and various techniques the investigators were able to isolate genetic variations that were shared between the 5 affected individuals. They ultimately narrowed down their search to a section of DNA containing 2,960 base pairs, which encoded a protein of 465 amino acids.

They decided to call that protein PARKIN.

PARKIN Protein. Source: Wikipedia

How much of Parkinson’s is genetic?

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Inhibiting LRRK2: The Denali Phase I results

Denali

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.


Wonder_Lake_and_Denali

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.

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Beware of the PINK-SNO(W) man!

There is a protein in most of the cells in your body called “PTEN-induced putative kinase 1″ (or simply PINK1). It plays an important role in keeping your cells healthy.

Genetic variations in the PINK1 gene have been shown to increase ones risk of developing Parkinson’s. 

This week researchers have identified a method by which the function of the PINK1 protein can be inhibited and this results in increased vulnerability to Parkinson’s. In this post, we will look at what PINK1 does, how it is inhibited, and what this could mean for the Parkinson’s community.


ampkmito-945x466

Mitochondria (green) in health cells (left) and in unhealthy cells (right).
The nucleus of the cell is in blue. Source: Salk Institute

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 which is the waste disposal system of each cell).

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

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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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AAV-PHP.B: The future is apparently now

In addition to looking at current Parkinson’s disease research on this website, I like to look at where technological advances are taking us with regards to future therapies.

In July of this year, I wrote about a new class of engineered viruses that could potentially allow us to treat conditions like Parkinson’s disease using a non-invasive, gene therapy approach (Click here to read that post). At the time I considered this technology way off at some point in the distant future. Blue sky research. “Let’s wait and see” – sort of thing.

So imagine my surprise when an Italian research group last weekend published a new research report in which they used this futurist technology to correct a mouse model of Parkinson’s disease. Suddenly the distant future is feeling not so ‘distant’.

In today’s post we will review and discuss the results, and look at what happens next.


Technological progress – looking inside the brain. Source: Digitial Trends

I have said several times in the past that the pace of Parkinson’s disease research at the moment is overwhelming.

So much is happening so quickly that it is quite simply difficult to keep up. Not just here on the blog, but also with regards to the ever increasing number of research articles in the “need to read” pile on my desk. It’s mad. It’s crazy. Just as I manage to digest something new from one area of research, two or three other publications pop up in different areas.

But it is the shear speed with which things are moving now in the field of Parkinson’s research that is really mind boggling!

Source: Pinterest

Take for example the case of Squalamine.

In February of this year, researchers published an article outlining how a drug derived from the spiny dogfish could completely suppress the toxic effect of the Parkinson’s associated protein Alpha Synuclein (Click here to read that post).

The humble dogfish. Source: Discovery

And then in May (JUST 3 MONTHS LATER!!!), a biotech company called Enterin Inc. announced that they had just enrolled their first patient in the RASMET study: a Phase 1/2a randomised, controlled, multi-center clinical study evaluating a synthetic version of squalamine (called MSI-1436) in people with Parkinson’s disease. The study will enrol 50 patients over a 9-to-12-month period (Click here for the press release).

Source: Onemednews

Wow! That is fast.

Yeah, I thought so too, but then this last weekend a group in Italy published new research that completely changed my ideas on the meaning of the word ‘fast’. Regular readers will recall that in July I discussed amazing new technology that may one day allow us to inject a virus into a person’s arm and then that virus will make it’s way up to the brain and only infect the cells that we want to have a treatment delivered to. This represents non-invasive (as no surgery is required), gene therapy (correcting a medical condition with the delivery of DNA rather than medication). This new study used the same virus we discussed in July.

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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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Nilotinib: the other phase II trial

DSK_4634s

In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.

What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.

Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.

In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the  ongoing Georgetown Phase II trial.


FDA-deeming-regulations

The FDA. Source: Vaporb2b

This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.

This is exciting and welcomed news.

What is Nilotinib?

Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).

What does any that mean?

Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.

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Oleuropein – “surely the richest gift of heaven?”

thomas-jefferson

The title of this post is a play on a Thomas Jefferson quote (“the olive tree is surely the richest gift of heaven“). Jefferson, the third President of the United States (1801 to 1809), was apparently quite the lover of food. During the Revolutionary War, while he was a U.S. envoy to France, Jefferson travelled the country. In Aix-en-Provence, he developed an admiration for olive trees, calling them “the most interesting plant in existence”.

Being huge food lovers ourselves, we here at the SoPD wholeheartedly agree with Jefferson. But we also think that olives are interesting for another reason:

They contain a chemical called Oleuropein.

In today’s post we’ll explore what is known about this chemical and discuss what it could mean for Parkinson’s disease.


olivve-pits

Olives. Source: Gardeningknowhow

The olive, also known by the botanical name ‘Olea europaea,’ is an evergreen tree that is native to the Mediterranean, Asia and Africa, but now found around the world. It has a rich history of economic and symbolic importance within western civilisation. And the fruit of the tree also tastes good, either by themselves or in a salad or pasta dish.

Traditional diets of people living around the Mediterranean sea are very rich in extra-virgin olive oil. Olives are an excellent source of ‘good’ fatty acids (monounsaturated and di-unsaturated), antioxidants and vitamins. Indeed, research has shown that the traditional Mediterranean diet reduces the risk of heart disease (Click here to read more on this).

preview

Olive oil. Source: Bonzonosvilla

There are also chemicals within the olive fruit that may have very positive benefits for Parkinson’s disease.

But before you rush out and gorge yourself on olives, we have one small piece of advice:

The chemical is called Oleuropein, and it is usually removed from olives due to its bitterness.

What is Oleuropein?

Oleuropein is a ‘phenylethanoid’ – a type of phenolic compound that is found in the leaf and the fruit of the olive. Phenolic compounds are produced by plants as a protective measure against different kinds of stress.

Oleuropein

Oleuropein. Source: Wikipedia

The main phenolic compounds found in olives are hydroxytyrosol and oleuropein – both of which give extra-virgin olive oil its bitter taste and both have demonstrated neuroprotective effects.

More research has been done on oleuropein so we will focus on it here (for more on hydroxytyrosol – please click here).

Oleuropein has been found to have many interesting properties, such as:

ijms-15-18508-ag

The many properties of oleuropein. Source: Mdpi

What neuroprotective research has been done on Oleuropein?

Thus far, most of the research addressing this question has been conducted on models of Alzheimer’s disease. The first study

PLos1

Title: Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit.
Authors: Diomede L, Rigacci S, Romeo M, Stefani M, Salmona M.
Journal: PLoS One. 2013;8(3):e58893.
PMID: 23520540                 (This article is OPEN ACCESS if you would like to read it)

The Italian researchers who conducted this study treated a microscopic worm model of Alzheimer’s disease with oleuropein aglycone. We should not that oleuropein aglycone is a hydrolysis product of oleuropein (a hydrolysis product is a chemical compound that is broken apart by the addition of water). The microscopic worm used in the study are called Caenorhabditis elegans:

c_elegans

Caenorhabditis elegans – cute huh? Source: Nematode

Caenorhabditis elegans (or simply C. Elegans) are tiny creatures that are widely used in biology because they can be easily genetically manipulated and their nervous system is very simple and well mapped out (they have just 302 neurons and 56 glial cells!). The particular strain of C. elegans used in this first study produced enormous amounts of a protein called Aβ42.

Amyloid beta (or Aβ) is the bad boy/trouble maker of Alzheimer’s disease; considered to be critically involved in the condition. A fragment of this protein (called Aβ42) begins clustering in the brains of people with Alzheimer’s disease. This clustering of Aβ42 goes on to form the plaques that are so characteristic of the Alzheimer’s affected brain.

The Italian researchers conducting this study had previously shown that oleuropein can inhibit the ability of Aβ42 to aggregate in cells growing in culture dishes (Click here to read more about that study), and they wanted to see if oleuropein had the same properties in actual live animals. So they chose the C. Elegans that had been genetically engineered to produce a lot of Aβ42 to test this idea.

In the C. Elegans that produce a lot of Aβ42 gradually become paralysed and their lives are shortened. By treating these worms with oleuropein, however, the Italian researchers found that there was less aggregation of Aβ42 (though the levels of the protein stayed the same), resulting in less plaque formation, and improved mobility (>50% reduction in paralysis) and survival compared to untreated Aβ42 producing C. Elegans.

Encouraged by this result, the researchers next moved on to studies in mice:

Plos2

Title: The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.
Authors: Grossi C, Rigacci S, Ambrosini S, Ed Dami T, Luccarini I, Traini C, Failli P, Berti A, Casamenti F, Stefani M.
Journal: PLoS One. 2013 Aug 8;8(8):e71702.
PMID: 23951225                   (This article is OPEN ACCESS if you would like to read it)

For this study, the Italian researchers used the genetically engineered TgCRND8 mice. These mice have a mutant form of amyloid precursor protein (which, similar to Aβ42, is associated with Alzheimer’s disease). In the brains of these mice, amyloid clustering begins at 3 months of age, and dense plaques are evident from 5 months of age. The mice also exhibit a clear learning impairment from 3 months of age.

By treating these mice with oleuropein aglycone, the researchers observed a remarkable reduction in plaques in the brain, and those that were present appeared less compact and “fluffy” (their very technical description, not ours). In addition, there was a reduction in the activation of astrocytes and microglia (the helper cells in the brain), indicating a healthier environment.

These same researchers have observed the same results in a rat model of Alzheimer’s disease in a report published the next year (Click here to read more about this).

Interestingly, the oleuropein treated TgCRND8 mice also displayed a major increase in autophagy activity. As we discussed in our previous post (Click here to read that post), autophagy is the rubbish disposal/recycling system of each cell, and increasing the activity of this system can help to keep cells health (particularly if there is a lot of a genetically engineered protein present!).

The Italian researchers repeated this study, and published the results this year, with an interesting twist:

JCBP

Title: Oleuropein aglycone and polyphenols from olive mill waste water ameliorate cognitive deficits and neuropathology.
Authors: Pantano D, Luccarini I, Nardiello P, Servili M, Stefani M, Casamenti F.
Journal: Br J Clin Pharmacol. 2017 Jan;83(1):54-62.
PMID: 27131215

In this study, the researchers tested the same genetically engineered mice, but with two different treatments:

  1.  Two much lower doses of oleuropein (4 and 100 times lower)
  2.  A mixture of polyphenols from olive mill concentrated waste water

The lowest dose of oleuropein (100 times less oleuropein than the previous study) did not provide any significant improvements for the mice, but the intermediate dose (only 4 times less oleuropein than the previous study) did provide significant benefits. These result indicate that there is a dose-dependent range to the beneficial properties of oleuropein.

The researchers also observed very similar beneficial effects from the mice drinking a mixture of polyphenols from olive mill concentrated waste water. Given these results, the investigators are now seeking to design appropriate conditions to perform a clinical trial to assess better the possible use of oleuropein (or a mix of olive polyphenols) against Alzheimer’s disease.

Ok, but what research has been done with oleuropein and Parkinson’s disease?

Unfortunately, not much.

A research group in Iran has looked at the effect of oleuropein in aged rodents and found an interesting result:

Iran
Title: Antioxidant role of oleuropein on midbrain and dopaminergic neurons of substantia nigra in aged rats.
Authors: Sarbishegi M, Mehraein F, Soleimani M.
Journal: Iran Biomed J. 2014;18(1):16-22.
PMID: 24375158                 (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators took twenty aged rats (18-month-old) and randomly assigned them to two groups: a treatment group (which received a daily dose of 50 mg/kg of oleuropein for 6 months) and a control group (which received just water). Following these treatments, the investigators found an increase in the activity of anti-oxidant agents (such as superoxide dismutase, catalase and glutathione) in the treatment group compared to control group. The treated rats also had significantly more dopamine neurons in the region of the brain affected by Parkinson’s disease (the substantia nigra). The investigators concluded that oleuropein consumption in a daily diet may be useful in reducing oxidative stress damage by increasing the antioxidant activity in the brain.

This first study was followed more recently by a report from a group in Quebec (Canada) who investigated oleuropein use in a cell culture model of Parkinson’s disease:

Oleu
Title: Oleuropein Prevents Neuronal Death, Mitigates Mitochondrial Superoxide Production and Modulates Autophagy in a Dopaminergic Cellular Model.
Authors: Achour I, Arel-Dubeau AM, Renaud J, Legrand M, Attard E, Germain M, Martinoli MG.
Journal: Int J Mol Sci. 2016 Aug 9;17(8).
PMID: 27517912              (This article is OPEN ACCESS if you would like to read it)

The researcher conducting this study wanted to determine if oleuropein could prevent neuronal degeneration in a cellular model of Parkinson’s disease. They exposed cells to the neurotoxin 6-hydroxydopamine (6-OHDA) and then investigated mitochondrial oxidative stress and autophagy.

What is mitochondrial oxidative stress?

Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.

Mitochondria

Mitochondria and their location in the cell. Source: NCBI

Oxidative stress results from too much oxidation. Oxidation is the loss of electrons from a molecule, which in turn destabilises the molecule. Think of iron rusting. Rust is the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. Given enough time, this results in the complete break down of objects made of iron.

1112dp_01rust_bustingrusty_bottom_of_door

Rust, the oxidation of metal. Source: TravelwithKevinandRuth

The exact same thing happens in biology. Molecules in your body go through a similar process of oxidation – losing electrons and becoming unstable. This chemical reaction leads to the production of what we call free radicals, which can then go on to damage cells. A free radical is an unstable molecule – unstable because they are missing electrons.

imgres

How free radicals and antioxidants work. Source: h2miraclewater

In an unstable format, free radicals bounce all over the place, reacting quickly with other molecules, trying to capture the much needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, to steal an electron. This leads to the “attacked” molecule becoming a free radical itself, and thus a chain reaction is started. Inside a living cell this can cause terrible damage, ultimately killing the cell.

Now if this oxidative process starts in the mitochondria, it can be very bad for a cell.

And what is autophagy?

Yes, the researchers also looked at autophagy levels in their cells. Autophagy is an absolutely essential function in a cell. Without autophagy, old proteins and mitochondria will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.

Think of autophagy as the waste disposal/recycling process of the cell.

Print

The process of autophagy. Source: Wormbook

Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material. The degraded waste material can then be recycled or disposed of by spitting it out of the cell.

Ok, so what did the researchers find?

Well, by pretreating the their cells with oleuropein 3 hours before exposing them to the neurotoxin, the investigators found a significant neuroprotective effect. There was a significant reduction in mitochondrial production of free radicals, and the investigators found an important role for oleuropein in the regulation of autophagy.

And the good news is that other research groups have observed similar beneficial effects of oleuropein in cell culture models of Parkinson’s disease (Click here to read more about that).

The bad news is: that is all the published research on oleuropein and Parkinson’s disease we could find (and we would be happy to be corrected on this if people are aware of other reports!).

So what does Oleuropein do in the brain?

This is a good question, but with so little research done in this area, it is hard to answer.

We know that oleuropein is well absorbed by the human body and that it is relatively stable (Click here to read more on this). In addition, it can cross the blood-brain-barrier – in rodents at least (Click here to read more on that).

Obviously (based on the research we described above), we know that oleuropein has anti-oxidant promoting activities. In addition, it appears to be doing something with regards to autophagy. And it may be regulating autophagy by acting as an inhibitor of mammalian target of rapamycin (mTOR) activation.

What is mTOR?

mTOR is a protein that binds with other proteins to form the nexus of a signalling pathway which integrates both intracellular and extracellular signals (such asnutrients, growth factors, and cellular energy status) and then serves as one of the central instructors of how the cell should respond.

For example, insulin can signal to mTOR the status of glucose levels in the body. mTOR also deals with infectious or cellular stress-causing agents, thus it could be involved in a cells response to conditions like Parkinson’s disease.

ncb2763-f11

Factors that activate mTOR. Source: Selfhacked

One important property of mTOR is its ability to block autophagy (the recycling process of the cell that we discussed above). Recently, the Italian researchers whose work we reviewed above, found that oleuropein can activate autophagy by blocking the mTOR pathway:

Onco

Title: Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight.
Authors: Rigacci S, Miceli C, Nediani C, Berti A, Cascella R, Pantano D, Nardiello P, Luccarini I, Casamenti F, Stefani M.
Journal: Oncotarget. 2015 Nov 3;6(34):35344-57.
PMID: 26474288                (This article is OPEN ACCESS if you would like to read it)

The researchers conducting this study found that treatment with oleuropein caused an increase in autophagy in both cell culture and in a mouse model of Alzheimer’s disease, and they demonstrated that it achieved this by blocking the mTOR pathway.

Has anyone ever looked at oleuropein in the clinic?

No, not to our knowledge (and we are happy to be corrected on this).

There have been six clinical trials of olive leaf extract (the majority of which is oleuropien), but none of them have been focused on any neurological conditions.

 

So oleuropein is safe then?

It is a widely available supplement that a lot of people use to help lower bad cholesterol and blood pressure, so yes it can be considered safe. But any decision to experiment with oleuropein should only be made in consultation with your regular medically trained physician.

Why? Because there are always caveats.

Importantly, individuals with low blood pressure and diabetes may suffer even lower blood pressure and blood glucose levels as a result of consumption of oleuropein. Oleuropein may also interact with other pharmaceutical drugs that are designed to lower blood pressure or regulate diabetes. Such interactions could be dangerous.

And this is a particularly important factor for Parkinson’s disease as up to 30% of people with Parkinson’s may be glucose intolerant (Click here to see our post on Parkinson’s & diabetes).

Those who experience symptoms such as headache, nausea, flu-like symptoms, fainting, dizziness, and other life threatening symptoms should medical attention immediately.

What does it all mean?

We are grateful to regular reader (Don) who brought oleuropein to our attention. It is a very interesting chemical and we are definitely intrigued by it. We would certainly like to see more research on oleuropein in models of Parkinson’s disease.

Attentive readers will have noticed that most of the research discussed above have been conducted in the last 5-10 years. This suggests that oleuropein research is still in its infancy, particularly with regards to research on neurological conditions. And we hope that by reporting on it here, we will be bringing it to the attention of researchers.

Oleuropein is extracted from all parts of the olive tree (the leaves, bark, root, and fruit). It forms part of the defence system of the olive tree against stress or infection. Perhaps we could apply some of its interesting properties to Parkinson’s disease.


EDITORIAL NOTE:  Under absolutely no circumstances should anyone reading the material on this website consider it medical advice. The information provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs and supplements discussed on this website are clinically available, they may have serious side effects. We urge caution and professional consultation before altering any treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here. 


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