Where LRRK2 leads, other genes follow!

LRRK2  - as I said before, mutations in this gene are the most common cause of Parkinson's. When I started work on fly models of Parkinson's, I was given some good advice: just focus on LRRK2 because (even though genetic forms of Parkinson's are only about 1% of cases) this will help more people than working on any other gene. A second good reason is that it looks as if LRRK2 forms of Parkinson's closely resemble all the other, the non-genetic forms, including adult onset Parkinson's, the kind that appears in people aged > 60 years old. Working on LRRK2 proved a highly successful strategy, and we could show that young flies with the G2019S mutation in this gene have a very overactive visual system [1]. Old flies with this mutation have, as you might expect, really bad vision because the nerve cells in their eyes have died.

But I still get comments saying is this work relevant to other forms of Parkinson's? So we have looked at a range of other forms, focussing on early-onset forms, mediated by genes called PINK1 and DJ1. This week, we were able to publish our paper showing that, like the young LRRK2-G2019S flies, young flies with mutations in these genes (PINK1 and DJ1) show overactive visual systems [2]. Actually, the method we used to analyse flies was made by miniaturising a technique devised to analyse the vision of babies. We called this FlyTV - its not quite as simple as in our cartoon, but works really reliably. It showed that detailed physiology of the eye in these two mutants is quite revealing, and suggests that we might be able to develop a scheme to monitor both the occurrence and the progression of "Parkinson's" in our flies using visual stimuli. Some of our data even suggests that the very fine visual changes we see may occur before any movement problems occur. Because we used the technique for babies' vision to study flies, we hope the technology might be developed and applied to adults. Our hope is that any early high levels of visual signalling might be a warning sign to start seeking medical advice.

FlyTV - The flies get to watch a TV showing stripy patterns changing several times a second. © Ryan West et al - see ref [2]

1] http://dx.doi.org/10.1093/hmg/ddu159

2] http://www.nature.com/articles/srep16933

News from the fly: LRRK2 and Golgi ??

And now I have a moment to relax, I want to comment on two lovely papers on dLrrk, the fly homolog of LRRK2 [1,2]. I found the similarities  fascinating.

First,  that they both showed, by independently making new mutants, that the dLrrk knock-out was lethal. Previous mutants that we thought were complete knock-outs, are now shown to still make enough protein for the flies to survive. We noted before that no  people with a lack of LRRK2 have ever been found, so it looks as if both the LRRK2 and dLrrk genes play an essential role in humans and flies, respectively.

Secondly, using the novel knock-outs, they could begin to identify what was wrong with the dLrrk knock-outs. The first paper [1] showed links to a number of sub-cellular organelles, mediated in part by the protein Rab9. Intriguingly, this links dLrrk to the retromer, recently identified as the home of VPS35. Mutations in VPS35 are another genetic cause of Parkinson’s. If both the LRRK2 and VPS35 mutations lead to Parkinson’s, it makes sense that we find them acting in a linked genetic pathways. It’s like finding pieces of a jigsaw puzzle, and recognizing that all the blue bits go to make the sky. When you start, its hard to find out how they fit together! In this case, the paper [1] suggests the ‘blue sky’ is part of the cell’s recycling machinery, returning unwanted proteins to the trans-Golgi network for breakdown and reuse.

Recycling by the Trans-Golgi network. Image used, with permission, from Gosh et al (2003) http://dx.doi.org/10.1038/nrm1050

The second paper [2] looked at the Golgi network in fly neurons, and found it was affected both by the dLrrk knock-out and by expressing the G2019S form of LRRK2. In a really good twist, the paper shows that it's the movement around the neurons of ‘Golgi-outposts’ that are affected, using lovely in-vivo movies (see one here), to watch the movement of dLrrk and the Golgi-outposts. Here’s another bit of our ‘blue sky’!

It’s really encouraging to see two papers come out focusing on a role for dLrrk in the Golgi system.

1] http://dx.doi.org/10.1242/dmm.017020    

2] http://www.jcb.org/cgi/doi/10.1083/jcb.201411033   

Learning and teaching Parkinson's

Hello again – No blogging as I was away, first at a Gordon Conference in the States, all about the cellular basis of Parkinson’s. One of the rules of a Gordon Conference is it is all confidential, which I respect, but I can say it was great to hear honest debate about the causes of Parkinson’s with lots of highly relevant  new data. I was particularly impressed by the way mouse work was catching up with the flies. In particular, I can mention a lovely presentation by Austen Milnerwood, as it is now published, showing that young mice with the LRRK2-G2019S mutation have an early hyperactivity phase, which is followed by degeneration of dopaminergic neurons [1]. Fascinating to see a mouse paper showing the same signs as our own fly work, published only last April [2].

Trend - the Gateway to Leaning fly neuroscience modelling health and disease

My other visit was to ‘Trend’ [3], where I was helping lead the fifth course in fly neuroscience (though my first visit). There I did 5 lectures 
on the ways that fly genetics can be used to work out the interconnections of disease genes and find novel approaches to therapy. Nice to be able to pass on ideas I’d be reading ad hearing recently. In the afternoons, we had practicals on the theme of flies modeling human disease, using flies with mutations in a gene associated with epilepsy, and other flies with mutations associated with Parkinson’s. There were 18 students on the course, and it was great to see their enthusiasm for neuroscience, and to see them getting stuck into the practical labs. They took off the flies at the end of the experiments to continue their exploration of the effects of these mutations. A very encouraging experience: Trend [3] is doing a marvelous job all across Africa, training students in top class science.

See you again soon!

chris

1] Volta et al, (2015) http://dx.doi.org/10.1016/j.parkreldis.2015.07.025

2] Afsari et al, (2014) http://dx.doi.org/10.1093/hmg/ddu159 


3] http://trendinafrica.org/blog-posts/5th-trendisn-neuroscience-school-well-underway/

Why do we need LRRK2? (Or what's wrong if we have no LRRK2?)

Hi again - as we said last time, once teams of geneticists had found one mutation in LRRK2, which was associated with Parkinson's,  they soon found many others. Many of these make LRRK2 act faster - what the geneticists call a 'gain of function'. More LRRK2 is worse, especially for dopaminergic neurons in the brain. More of why this might be - next time.

If you wonder about how LRRK2 mutations lead to Parkinson's, how about taking a moment to ponder what happens if LRRK2 didn't exist? What happens with less LRRK2, or even none at all? Is LRRK1, the nearest related enzyme enough to make up for it, or do LRRK1 and LRRK2 do different things?

Don't LRRK1 and LRRK2 look similar in this diagram of their structure?
[from http://www.bio.unipd.it/~bubacco/assets/images/lrrk1-lrrk2a.jpg ]

As far as I can determine, and I always ask the geneticists, none has found anyone without LRRK2. Maybe people with such a 'loss of function' mutation would have different symptoms to people with Parkinson's. Maybe looking at people with Parkinson's is just the wrong place to look, but geneticists are busy screening for all sorts of diseases, and screening controls with no illness.

Ask the fly - a fly with no dLRRK (its equivalent to both LRRK1 and LRRK2) has a shorter lifespan, so dLRRK at least seems to be beneficial. Recent reports suggest that rats with no LRRK2 have lung and kidney problems, while animals fed with inhibitors of LRRK2 also have these deficits. [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080705 , http://stm.sciencemag.org/content/7/273/273ra15.short ]. Maybe no LRRK2 is fatal to humans during development, so that you really need enough LRRK2 to live.

What does this mean for Parkinson's? It suggests you need to get the dose of any LRRK2 inhibitor just right - too little and you have no effect on brain function, too much and you will have lung or kidney problems.

See you again soon - we can chat about LRRK2 inhibitors !

chris

More LRRK2 mutations?

Welcome back - last time we mentioned that a mutation in LRRK2 was the most common cause of Parkinson's. This was the G2019S change.

So what else happens to LRRK2 in Parkinson's? Well once the gene was sequenced, and the G2019S mutation found, everyone stated looking for other mutations. Here's a picture of the mutations found by 2006, just 2 years after the G2019S was found.

Mutations in LRRK2, as known in 2006, (Modified after Taylor et al, Trends Mol Med 12:76-82)

In red, are the mutations definitely causing Parkinson's; in blue those thought to be risk factors. Right next to our friend G2019S are two more mutations, I2020T and I2012T. Like G2019S, these interfere with the ability of LRRK2 to split a chemical ATP - the energy currency of the cell - and use this to turn on other enzymes. The other mutations shown in red (R1441C, R1441G and Y1699C) interfere with the ability of LRRK2 to split another molecule, GTP, a molecular 'traffic light'. This amplifies the effect of LRRK2 signalling. 

Although its nearly 10 years since these mutations were found, its still not known where in cells or neurons signalling by LRRK2 occurs, or even where in the brain and the rest of the body the protein is found. Nor do we yet know the targets of the molecular switches. My colleagues around the world have made lots of suggestions, backed up with experiments, but not yet found much consensus.

One way forward - lets ask the fly? Maybe a curious approach, but one with exciting possibilities!

See you again soon

chris

Welcome to the world of LRRK2

LRRK2 - never heard of it ? Probably not.

Its quite important as mutations in this gene are the most common cause of Parkinson's. Indeed some reckon that up to 40% of people with Parkinson's could have the disease because of just one mutation in this gene. This mutation swaps the 2019th amino acid, from G to S.

Its important to people in Tunisia, where up to 40% of people with PD carry this mutation. Probably this means the mutation may have started in Tunisia. In Yorkshire, UK, my colleague Oliver looked for G2019S mutations, and could not find a single one in over 1000 people, so its not so common where I live.


Its quite important to Sergei Brin - maybe you know his firm? Google? He was found to have the the G2019S mutation from his mother, and the brave man has both written about it and given a big donation to try and help understand how this G to S change leads to Parkinson's.


Its quite important to me, as I work on the cause of Parkinson's, by looking at how flies engineered for Parkinson's related genes work. I'm just amazed at how these insects can give us insights into the effects of all sorts of mutations. My hope is that the fact that we are all made up of similar cells and nerves means that what we find in the fly, with its great experimental genetics, will be useful in the clinic.

All for now - see you again soon

chris



PS. Even if you know that you have the mutation, it doesn't mean you will get Parkinson's. Curious?