Dear Doctor
In 2010, more than 800 publications resulted from studies on the LRRK2 (Leucine-rich repeat kinase 2) protein. This year looks like this focus will be continued as over 100 publications have already appeared in the first 6 weeks of 2011. Why the interest?
LRRK2 (also now classified as PARK8) became of great interest in 2004 when it was identified as the second autosomal dominant Parkinson's disease (PD) gene involving a toxic gain of function. Mutations in the LRRK2 gene account for approximately 6% of all familial cases of PD as well as 2% of spontaneous cases. The LRRK2 gene encodes a protein that is part of a larger multidomain protein with GTPas and kinase domains. Only a few of its substrates have been identified, so its role in triggering this disease remains an enigma. The best evidence suggests that mutated LRRK2 is toxic due to an enhanced kinase activity (Lee et al, Nature Med 16:998-1000, 2010). |
| A novel approach to generating animal models of Parkinson's disease |
|
A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2. Dusonchet et al, The Journal of Neuroscience 2011 31:907-912 Abstract
Producing transgenic animals is now routine, but their value is often limited by inability to target expression to specific groups of cells, including neurons, as well as the complexity of using animals other than mice. In this brief communication, these researchers have used an alternate viral approach to deliver a mutant LRRK2 gene to neurons within the nigrostriatal system of adult rats. The result is a useful rat model of PD that can be generated quickly in most laboratories.
|
|
LRRK2 kinase inhibition is protective in PD animal models |
Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease Lee et al, Nature Medicine 2010 Sep;16(9):998-1000 Abstract
That LRRK2 mutations generate a toxic gain of function, possibly as a result of increased kinase activity, suggests that specific kinase inhibitors might prevent LRRK2-induced degeneration. This study provides evidence in both in vitro and in vivo models that the neuronal degeneration seen in these models is due to the enhanced kinase activity of the mutant LRRK2 protein. It also points the way to potential treatments for this form of PD. |
| Two new reviews suggest intersecting pathways for LRRK2 and alpha-synuclein |
Leucine-rich repeat kinase 2 and alpha-synuclein: intersecting pathways in the pathogenesis of Parkinson's disease? Greggio et al, Molecular Neurodegeneration 2011 6Jan 18;6(1):6 Abstract
This excellent review discusses recent literature on these two genes which both cause dominantly inherited PD, and looks for any evidence that suggests a functional link between them. The authors provide a cogent argument for an action of LRRK2 in promoting alpha-synuclein aggregation. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease Cookson MR, Nature Reviews, Neuroscience Dec 2010 11(12):791-7 Abstract
In this review, Cookson also argues the case for an intersection between LRRK2 and alpha-synuclein. He adds the possible involvement of tau protein in trying to understand the disease process. |
