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