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