New research – new targets of Lrrk2

This is Sergey Brin.

He’s a dude.

Having brought us ‘Google’, he is now turning his attention to other projects.

One of these other projects is close to our hearts: Parkinson’s disease.

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In 1996, Sergey’s mother started experiencing numbness in her hands. Initially it was believed to be RSI, but then her left leg started to drag. In 1999, following a series of tests, Sergey’s mother was diagnosed with Parkinson’s disease. It was not the first time the family had been affected by the condition: Sergey’s late aunt had also had Parkinson’s disease.

Both Sergey and his mother have had their genome scanned for mutations that increase the risk of Parkinson’s disease. And both of them discovered that they were carrying a mutation on the 12th chromosome, in a gene called Leucine-rich repeat kinase 2 or Lrrk2.

Not everyone with this particular mutation will go on to develop Parkinson’s disease, but Sergey has decided that his chances are 50:50. Being one of the founders of a large company like Google, however, has left Sergey with resources at his disposal. And he has chosen to focus some of those resources on Lrrk2 research (call it an insurance  policy).

Today, the fruits of some of that research has been published and the results are really interesting:

 

Title: Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases
Authors: Martin Steger, Francesca Tonelli, Genta Ito, Paul Davies, Matthias Trost, Melanie Vetter, Stefanie Wachter, Esben Lorentzen, Graham Duddy, Stephen Wilson, Marco AS Baptista, Brian K Fiske, Matthew J Fell, John A Morrow, Alastair D Reith, Dario R Alessi, Matthias Mann
Journal: Elife 2016;10.7554/eLife.12813
PMID: 26824392  (This report is openly available for reading on the Elife website)

So what is Lrrk2?

Also known as dardarin (Basque for ‘trembling‘), Lrrk2 is a gene in our DNA that is responsible for making an enzyme. That Lrrk2 enzyme is involved in many different aspects of cell biology. From cellular remodeling and moving (‘trafficking’) various proteins around in the cell, to protein degradation and stabilization, Lrrk2 has numerous roles.

Discovered in 2004, Lrrk2 was quickly associated with Parkinson’s disease because mutations in this gene are amongst the most common in ‘familial Parkinson’s‘ (where an inherited genetic mutation is present in the sufferer; accounting for about 10-20% of all cases of Parkinson’s disease). The most common mutation of LRRK2 gene is G2019S, which is present in 5–6% of all familial cases of Parkinson’s disease, and is also present in 1–2% of all sporadic cases.

Curiously, mutations in Lrrk2 are also associated with increased risk of Crohn’s disease and cancer.

The structure of Lrrk2 and where various mutations lie. Source: Intech

Given the association with Parkinson’s disease, there have been attempts to develop inhibitors of Lrrk2 as a means of treating the condition. These efforts, however, have been hampered by a poor agreement as to which proteins are interacting with Lrrk2.

The goal of the current study was to identify the key proteins that Lrrk2 acts upon.

What did they discover?

Using various techniques to accomplish their task, the scientists began with 30,000 possible targets and gradually whittled that number down to a small group of Lrrk2 targets.

Most importantly, they found that Lrrk2 is deactivating certain proteins that are called ‘Rabs’. The Rab family are heavily involved with trafficking (and that’s not the mafia drug variety!). Trafficking in cells in moving proteins around within the cell itself. And Lrrk2 was found to deactivate 4 Rab family members (3, 8, 10 and 12).

This is a very important result as not only does it provide us with novel Lrrk2 targets, but it also offers us an excellent tool with which we can determine if Lrrk2 inhibitors are actually working  – a functioning Lrrk2 inhibitor will lower the activity of Rab 3, 8 10 & 12 and this can be measured.

The results represent a major leap forward in our understanding of Lrrk2 and a significant return on investment for one Mr Sergey Brin.