Nuclear factor erythroid 2–related factor 2 (or NRF2) is a protein in each of your cells that plays a major role in regulating resistance to stress. As a result of this function, NRF2 is also the target of a lot of research focused on neuroprotection.
A group of researchers from the University of British Columbia have recently published interesting findings that point towards to a biological pathway that could help us to better harness the beneficial effects of NRF2 in Parkinson’s.
In today’s post, we will discuss what NRF2 is, what the new research suggests, and how we could potentially make use of this new information.
Rusting iron. Source: Thoughtco
In his book ‘
xidation nibbles more slowly – more delicately, like a tortoise – at the world around us, without a flame, we call it rust and we sometimes scarcely notice as it goes about its business consuming everything from hairpins to whole civilizations”
And he was right on the money.
Oxidation is the loss of electrons from a molecule, which in turn destabilises that particular molecule. It is a process that is going on all around us – even within us.
Iron rusting is the example that is usually used to explain oxidation. Rust is the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. And given enough time, this results in the complete break down of objects made of iron.
The combustion process of fire is another example, albeit a very rapid form of oxidation.
Oxidation is one half of a process called Redox – the other half being reduction (which involves the gaining of electrons).
The redox process. Source: Academic
Here is a video that explains the redox process:
Now it is important to understand, that oxidation also occurs in biology.
Molecules in your body go through the same process of 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.
What is a free radical?
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.
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?
It seems everyday we read stories in the media about the benefits of these things called antioxidants. We are repeatedly told that we ‘need more antioxidants in our diet’, because they will help to stave off debilitating conditions like Parkinson’s disease.
Last week, however, a study was published which indicates that this may not be the case.
In todays post we look at antioxidants and their impact on Parkinson’s disease.
Berries are a wonderful source of antioxidants. Source: Steroidal
Antioxidants are one of those subjects that is often discussed, but not well understood. So before we review the study that was published last week, let’s first have a look at what we mean when we talk about antioxidants.
What is an antioxidant?
An antioxidant is simply a molecule that prevents the oxidation of other molecules.
OK, but what does that mean?
Well, the cells in your body are made of molecules. Molecules are combinations atoms of one or more elements joined by chemical bonds. Atoms consist of a nucleus, neutrons, protons and electrons.
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.
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.
What is a free radical?
A free radical is an unstable molecule – unstable because they are missing electrons. They react quickly with other molecules, trying to capture the needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, stealing 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.
Antioxidants are thus the good guys in this situation. They are molecules that neutralize free radicals by donating one of their own electrons. The antioxidant don’t become free radicals by donating an electron because by their very nature they are stable with or without that extra electron.
How free radicals and antioxidants work. Source: h2miraclewater
What are good sources of antioxidants?
While human being are pretty poor at producing antioxidants, plants produce LOTS! Thus vegetables and fruits are a fantastic source of antioxidants.
Sources of antioxidants (no. 3 is our favourite). Source: DrAxe
The Oxygen radical absorbance capacity (ORAC) score mentioned in the figure above is a method of measuring the antioxidant capacity of various substances. For comparative sake, a piece of tofu has an ORAC score of approximately 90, a beef steak has an ORAC score of approximately 10, and a ‘Redbull’ energy drink has an ORAC score of 0 (as they all have very few antioxidants – Source:Superfoodly).
A source of major antioxidants are vitamins (such as beta-carotene, vitamin C, and vitamin E). Vitamins are essential nutrients that our bodies needs (in small amounts) to function properly. Many of them are also potent antioxidants.
Vitamin C (or ascorbic acid), in particular, is a powerful antioxidant and it is found in both animals and plants. Unfortunately for humans, however, one of the enzymes needed to make ascorbic acid was lost by a genetic mutation during primate evolution, and so we must obtain it from our diet (eat lots of oranges folks).
How could antioxidants work for Parkinson’s disease?
Postmortem analysis of the brains of people who had Parkinson’s disease has revealed numerous signs of oxidative damage, and this has lead to many researchers hypothesising that oxidation is a key component of the disease.
So what research was published last week?
The results of this study:
Title: Intake of antioxidant vitamins and risk of parkinson’s disease.
Authors: Hughes KC, Gao X, Kim IY, Rimm EB, Wang M, Weisskopf MG, Schwarzschild MA, Ascherio A.
Journal: Movement Disorders. 2016 Oct 27. doi: 10.1002/mds.26819.
In this study, the investigators wanted to look at the consumption of antioxidant vitamins and the risk of developing Parkinson’s disease. In order to do this, they needed large pools of medical data that they could analyse. They used the databases from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) in the USA.
NHS study was started in 1976 when 121,700 female registered nurses (aged 30 to 55 years) completed a mailed questionnaire. They provided an overview of their medical histories and health-related behaviours. The HPFS study was established in 1986, when 51,529 male health professionals (40 to 75 years) responded to a similar questionnaire. Both the NHS and the HPFS send out follow-up questionnaires every 2 years.
The investigators in the current study, removed the data from people who reported ‘implausible total energy intake at baseline (<660 or >3,500 kcal/day for women and <800 or >4,200 kcal/day for men)’, missed reporting for any survey, or had a diagnosis of Parkinson’s disease at the start of the study. This left them with the survey results of 80,750 women and 48,672 men to analyse.
From these pools of subjects, they found a total of 1036 people with Parkinson’s disease (554 in HPFS and 482 in NHS). When the investigators looked at antioxidant vitamin consumption, they found that vitamin E was not associated with an increased or decreased risk of Parkinson’s disease. Vitamin C intake showed indications of reducing the risk of developing Parkinson’s, but this not significant.
The investigators concluded that their results do not support the hypothesis that consumption of antioxidant vitamins reduces the risk of Parkinson’s disease.
What about other Parkinson’s disease research on antioxidants?
There have been several clinical trials for antioxidants and Parkinson’s disease. Of particular interest has been the research surrounding Coenzyme Q10 (also known as ubiquinone and ubidecarenone).Coenzyme Q10 is an antioxidant that exhibited positive preclinical results for Parkinson’s disease, and this led to several large clinical trials:
Title: A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.
Authors: Parkinson Study Group QE3 Investigators., Beal MF, et al.
Journal: JAMA Neurol. 2014 May;71(5):543-52.
This article reported the results of a phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites, consisting of 600 participants. While Coenzyme Q10 was safe and well tolerated by the subjects in the study, it demonstrated no evidence of clinical benefit.
One justified critique of this study, however, was the variety of subjects with Parkinson’s disease involved in the study. It has been suggested that a clinical trial should be performed with coenzyme Q10 in people with Parkinson’s disease who have a proven mutation in the PINK1 gene as these are the subjects who are most likely to benefit from this approach. That would be an interesting trial.
So what does it all mean?
Well, the study published last week needs to be replicated with another large database before any serious conclusions can be made. For all the hype around antioxidants, however, there is a worrying lack of supporting evidence that they actually have any effect (in the case of lung cancer there are even suggestions that some vitamin antioxidants could exacerbate the situation – click here for more on this).
The results of the study reviewed above do suggest that our view of oxidation in Parkinson’s disease needs to be re-addressed. It may be that oxidation may simply be an end step in the condition, and trying to block it with antioxidants is fruitless.
It should be noted that we are not suggesting here that people should stop taking antioxidants – they are an important part of any balanced diet, necessary for normal biological functioning. We are simply presenting the evidence that some of the hype surrounding their potential is unfounded.
As usual, as more information comes to hand, we shall present it here. Watch this space.
The banner for todays post was sourced from Pinkhope