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/