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