Blogging with Parkinson's

A personal perspective on Young Onset Parkinson's


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How PINK1 mutations cause Parkinson’s

If we know what causes Parkinson’s, and how, we can understand it better. If we understand it better, we might be able to prevent it, or treat it, or stop it in its tracks, or even roll it back as if it never ever happened (the last seems unlikely). But understanding is key.

And that’s what this science story is about. Researchers in Dundee have used an insect version of the gene PINK1, known to be one of the genes whose mutation can cause Parkinson’s, to work out how the mutation causes Parkinson’s. A summary of the research is given in a Royal Society news article.

And even better, they’ve published it in the Royal Society’s new open format – which means, dear reader, that you, too, can plough through impenetrable scientific jargon in the hope of extracting some… er, hope. Actually, it isn’t that bad. There’s quite a bit of plain prose that tells you pretty much everything you might want to know. Even so, I have endeavoured to select the key elements for your delight and delectation.

Mutations in the protein kinase PINK1 (PTEN-induced kinase 1) gene cause hereditary Parkinson’s disease. Patients harbouring PINK1 mutations typically present with early-onset Parkinson’s disease, with a mean age of onset in their 30s.

Extract from the Introduction to “Discovery of catalytically active orthologues of the Parkinson’s disease kinase PINK1: analysis of substrate specificity and impact of mutations “ by Helen I. Woodroof, Joe H. Pogson, Mike Begley, Lewis C. Cantley, Maria Deak,David G. Campbell, Daan M. F. van Aalten, Alexander J. Whitworth, Dario R. Alessi1 and Miratul M. K. Muqit, published in Open Biology, November 2011.

… which is quite young. So we’re talking definite young onset here; I suppose it’s possible that I could have a PINK1 mutation. So what does PINK1 do?

The function of PINK1 remains poorly understood, although, in mammalian cells, several studies suggest that PINK1 controls another Parkinson’s disease-associated enzyme, namely the parkin E3 ligase, by recruiting it to the mitochondrial membrane through an as-yet-undefined mechanism.

Extract from the Introduction, ibid.

They’re not sure. However, it has been determined that knocking out PINK1 in mice has no observable effect – but in fruit flies, the lack of a functional PINK1 causes Parkinsonian symptoms, “including motor deficits, neuronal loss and mitochondrial abnormalities.”

It turns out that the insect PINK1 is easier to work with in the lab than the human variant. The researchers were able to establish that “most Parkinson’s disease-associated missense mutations ablate or markedly inhibit PINK1 kinase activity.” I think this means that mutations in the PINK1 gene that cause Parkinson’s are likely to be related to the kinase activity of PINK1.

Which begs the question, “What is a kinase?” In answer, Wikipedia says that a kinase is “a type of enzyme that transfers phosphate groups from high-energy donor molecules […] to specific substrates.”

The article goes on to describe the experimental process and its results.

We determined the effects of Parkinson’s disease-associated mutations on PINK1 catalytic activity by selecting 14 […] mutations that lead to early-onset Parkinson’s disease […]. All bar one of the selected mutations are located within the kinase domain […].

[…]

Our results suggest that missense PINK1 mutations situated within the kinase domain exert their Parkinson’s disease-causing effects by markedly suppressing kinase activity […]. This emphasizes the importance of identifying the key physiological substrates of PINK1 in order to understand how the loss of kinase activity leads to neurodegeneration in Parkinson’s disease.

Extract from the Results section, ibid.

After a short discussion of the kinase inhibition treatments that are currently being developed for other diseases and the possibility of such treatments inducing Parkinson’s (the risk is judged to be low),  they offer their conculsions:

In conclusion, we report for the first time a novel method to express an active form of PINK1. This has enabled us to develop an assay to quantitatively assess PINK1 activity and investigate its substrate specificity. Our work suggests that, with the exception of the C125G mutation [which lies outside of the kinase domain], all other Parkinson’s disease mutations assessed are likely to exert their disease-causing effects by suppressing kinase catalytic activity. These observations emphasize the importance of PINK1 kinase activity in preventing the onset of Parkinson’s disease, and that the key challenge in future will be to identify PINK1 substrates and study the relevance of these in Parkinson’s disease. We hope that the results presented in this study will aid with assaying PINK1 catalytic activity and in the hunt for substrates of this enzyme.

Extract from the Results section, ibid.

This study may not present any solutions to the problem of Parkinson’s, but it does contain a new piece of the jigsaw that will help the scientific community understand the disease and, hopefully, create new and effective treatments in the future.

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John Harding, “What we did on our holiday”

This is a novel that describes advanced Parkinson’s in a family member. It is an “end of life” Parkinson’s book, not unlike Franzen’s The Corrections or Mistry’s Family Matters. As such, it can be a difficult read. Nick’s father is in the advanced stages of Parkinson’s. He is severely disabled, although his wife seems bizarrely grateful that “he hasn’t got the shaking kind” (there: myth number one about Parkinson’s debunked).

Nick and his wife, Laura – and, predictably, not all is completely tickety-boo in that relationship – decide to take Nick’s parents on holiday to Malta, where Dad (whose name is Jim) was stationed during World War II. The novel opens with the aeroplane journey, which sets the scene by introducing the awful difficulties of dealing with an aged parent’s disabilities and the frustrations experienced by each of the group. Well, all of them except for Dad. Dad finds it difficult to express himself coherently. Dad has, essentially, lost his voice as a character… or has he? Glimmers of personality emerge now and then, the more achingly precious for their rarity, and the ending rests upon a full understanding of a request from father to son. Continue reading


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High-powered MRI may provide Test for Parkinson’s

One of the peculiarities of Parkinson’s Disease is that there is no definitive test for it. To be sure, you get a battery of tests on the NHS, but they (blood tests and an “ordinary” MRI scan) are all to check for alternative diagnoses, not to see if you actually do have Parkinson’s. There is a scan which makes use of a radioactive chemical called Ioflupane (123I), or DaTSCAN – this makes dopamine transmitters visible to a gamma camera, and so should allow levels of dopamine to be registered. However, it is not a conclusive test and is often considered too expensive. When I asked my consultant about it, he was quite dismissive (whether because it was unlikely to work in my case or because of the cost, I am not sure).

Only yesterday, I came across an article that suggested that many cases of Parkinson’s were misdiagnosed.  It seems to have been news in 2006. Which is quite a long time ago; the implication in the article is that GPs (family doctors) lacked experience with Parkinson’s and that a specialist should make the diagnosis (they do this by knowing what to look for – it’s quite vague but experience, it seems, helps a lot).

Anyway. Back to the matter referred to in the title. A research institute in Canada has a 7 Tesla MRI machine – exceptionally strong for a medical design (standard medical MRIs are around 1.5 Tesla) – which allows them to get a particularly high-definition scan of the brain. Apparently, it is possible to see the difference between a Parkinsonian brain and a normal one using this equipment. Continue reading


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Telegraph article: Richard Collins on Hill Walking and Parkinson’s

It seems that I’m not the only Young Onset Parkinsonian drawn to the hills. Richard Collins, former teacher, novelist, and, regrettably, fellow-traveller on the long distance Parkinson route, also finds hill walking enjoyable and beneficial. It must be a combination of the fresh air, the exercise, the exhilarating scenery and, not least, the sense of achievement – something that is really worth seeking out when your personal horizons seem to be closing in on you with a diagnosis of Parkinson’s.

But enough of my waffle. Read the article:

“Parkinson’s disease left me with a mountain to climb”,
Richard Collins, published in The Telegraph on 21 November 2011

And, while you’re at it, check out his novels:


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Multi-Tasking, Dopamine, Tiredness and Marie Claire

I don’t usually pay much heed to what fashion magazines say, but flicking through the pages of November’s edition of Marie Claire (bought partly because the free tube of hand cream on the front reminded me of a tube of paint), I came across a snippet that neatly drew together a few things I’ve heard and read elsewhere.

5.TOO MUCH MULTITASKING
[…]
Simultaneously reading your email, chatting on the phone and doing bottom firming exercises at your desk isn’t necessarily productive. ‘Multitasking overstimulates the dopamine system,’ says Professor Paul Gilbert, consultant psychologist and author of The Compassionate Mind […]. ‘Dopamine is a chemical linked to rewards, drive and vitality and is easily depleted. When stores are low, this can lead to listlessness and depression,’ he explains. Professor Gilbert suggests balancing dopamine release by stimulating your endorphin system – the positive emotional pathway in the brain responsible for well-being. Try gentle activities such as gardening, hiking or meditation.

from “12 Reasons You’re Tired All The Time,” by Anna Magee, Marie Claire, November 2011

Potatoes. Harvested.

Continue reading