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
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?
Recently scientists have found a possible link in the curious relationship of red hair, melanoma and Parkinson’s disease.
It involves red headed mice (not a typo – you read that correctly).
In today’s post we will discuss the new research and explain what it means for Parkinson’s disease.
Red or ginger hair. Source: theLocal
We have previously discussed the curious association between red hair and Parkinson’s disease (Click here for that post).
We have also previously discussed the curious association between melanoma and Parkinson’s disease (Click here for that post).
Melanoma. Source: Wikipedia
Basically, people with red hair are more vulnerable to Parkinson’s disease that dark haired people, and people with a history of melanoma (skin cancer) are more likely to develop Parkinson’s disease than people with no history.
And given that people with red hair are generally more vulnerable to melanoma that dark haired people, you can understand why scientists have recently been very interested in this curious triangle of seemingly unrelated biological features.
Recently, however, scientists in Boston (USA) have provided evidence that the genetic mutation which causes red hair and increases the risk of melanoma, might also make the brain more vulnerable to Parkinson’s disease.
Red hair is caused by a genetic mutation?
Before we answer this question: the word ‘mutation’ carries a negative connotation thanks to it’s use in popular media and films. In biology, researchers prefer to use the word genetic ‘variation’. And EVERYONE has variations. They are what makes each of us unique. A father will pass on many of his own genetic variations to his son, but there will also be 50-100 spontaneous variations. And this is how, red hair can sometimes pop up in a family with little history of it.
Ok, so red hair is caused by a genetic variation?
Red hair, which occurs naturally in 1–2% of the general population (though there are some regional/geographical variation), results from one of several genetic variations. Approximately 80% of people with red hair have a variation in a gene called melanocortin-1 receptor (or MC1R). Another gene associated with red hair is called HCL2 – ‘Hair colour 2’.
So what did the researchers find?
Title: The melanoma-linked “redhead” MC1R influences dopaminergic neuron survival.
Authors: Chen X, Chen H, Cai W, Maguire M, Ya B, Zuo F, Logan R, Li H, Robinson K, Vanderburg CR, Yu Y, Wang Y, Fisher DE, Schwarzschild MA.
Journal: Ann Neurol. 2016 Dec 26. doi: 10.1002/ana.24852. [Epub ahead of print]
In their study, the researchers have investigated mice that carry a mutation of the MC1R gene (thus inactivating the gene – and yes, these mice have red/ginger fur!). They noticed that the mice displayed a progressive decline in their locomotor activity, moving around significantly less than non-red furred control mice at 8 months of age. The MC1R mutant mice also displayed a reduction in the number of dopamine producing neurons in the brain, when compared to the non-red furred controls (dopamine a chemical in the brain that helps to regulate movement).
The MC1R mutant mice were more vulnerable to toxin induced models of Parkinson’s disease (both 6OHDA and MPTP), but (most interestingly) when the researchers used a substance that binds to MC1R and initiates a response (an MC1R agonist called BMS-470539) they found that this treatment improved the survival of the dopamine producing cells in the brain.
The researchers are now seeking to further understand how the loss of MC1R renders the dopamine cells more vulnerable, and follow up the finding that MC1R agonists are neuroprotective.
Has there ever been any other evidence to suggest that MC1R is neuroprotective?
No. To our knowledge this is the first evidence that targeting MC1R could be a novel therapeutic strategy in a brain related condition (there has been some evidence of MC1R activation having beneficial effects in other parts of the body – click here for more on this).
And there are some indications as to how this positive effect could be working:
Title: Melanocortin-1 receptor signaling markedly induces the expression of the NR4A nuclear receptor subgroup in melanocytic cells.
Authors: Smith AG, Luk N, Newton RA, Roberts DW, Sturm RA, Muscat GE.
Journal: J Biol Chem. 2008 May 2;283(18):12564-70.
In this study, the researchers found that activating MC1R increases the levels of a protein called NR4A2 (or Nurr1). Nurr1 is a protein involved in the development and maintenance of dopamine producing neurons, and numerous recent studies have suggested that it is neuroprotective for these cells as well (Click here to read more on this).
So what does it all mean?
For some time there has been a curious link between people with red hair, melanoma and Parkinson’s disease. Now researchers in Boston have provided new evidence that the link exists, but they have also highlighted a new pathway via which novel therapies for Parkinson’s disease might be researched and developed. Not a bad day at the office.
The banner for today’s post was sourced from Fancy mice