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