Which LRRK2 kinase substrates identified to date are most likely to be true physiological substrates? What limitations/barriers hinder identification of novel substrates?

Post-Translational Modification, Targeting Post-translational Modification, PARK8 (LRRK2)

Mutations in the gene coding for the putative kinase LRRK2 represent some of the most prevalent genetic factors yet linked to Parkinson’s disease, but how these alterations lead to PD-related pathogenesis remains unclear. A prevailing hypothesis centers around the belief that mutations lead to a toxic gain-of-function in kinase activity; thus, identification of substrates of LRRK2 kinase activity is essential to determining the pathogenic mechanism of LRRK2.

Responses:
LRRK2 Upstream and Downstream
Brian K. Fiske, MJFF
26 Jun 2009 04:16 PM EST
Despite the clear and strong genetic links between LRRK2 and PD, we still know little about its actual physiological function in the cell. Evidence demonstrating that pathogenic mutations in LRRK2 ... 
Synuclein as a LRRK2 substrate
Mark Cookson, NIH
9 Jul 2009 04:53 PM EST
A recent article by Qing et al proposing that synuclein is a direct substrate of LRRK2 illustrates many of the reasons why progress in identifying substrates can be difficult - for every exciting new ... 
Challenges in LRRK2 substrate identification
Andrew B West, UAB
9 Jul 2009 08:10 PM EST
In thinking about LRRK2 kinase substrates, one first ponders whether LRRK2 even possesses the ability to phosphorylate other proteins in cells, and that LRRK2 kinase activity is not exclusive to ... 
Synuclein as a LRRK2 substrate
Jean-Marc Taymans, KU Leuven
20 Jul 2009 11:16 AM EST
The relationship between LRRK2 and alpha-synuclein, two genes linked to familial PD in an autosomal dominant manner, is still largely unknown. Although studies focussing on the relationship ... 
LRRK2 as a LRRK2 substrate?
Elisa Greggio, UNIPD, et al.
10 Sep 2009 01:17 PM EST
Two main observations have driven researchers to focusing on the identification of LRRK2 substrates: first, the most common LRRK2 mutation G2019S enhances kinase activity and, second, this activity ... 
Responses: 1
Substrate specificity and inhibitors of LRRK2
R. Jeremy Nichols, MRC
25 Sep 2009 08:02 AM EST
For some time, researchers used autophosphorylation of LRRK2 or transphosphorylation of the generic MBP substrate as a readout of LRRK2 activity.  We undertook a KESTREL (kinase substrate ... 
The Utility of a LRRK2 Dimer
Andrew B West, UAB
14 Oct 2009 03:40 PM EST
In 2007, our group and others began developing ways to visualize LRRK2 conformations using native PAGE and gel filtrations, and found that a proportion of LRRK2 protein is present as dimer-sized ... 
Independent datasets that agree with each other...LRRK2 autophosphorylation in ROC
Mark Cookson, NIH
15 Oct 2009 11:37 AM EST
Brief update; the Iwatsubo group in Tokyo has just published a paper in Biochemistry identifying four sites in the ROC domain that overlap with our own analyses: Ser1403, Thr1404, Thr1410 and ... 
The substrate hunt continues...
Holli Kawadler, MJFF
25 Jan 2010 09:14 PM EST
A recent publication from Mark Cookson's group suggests that 4E-BP is likely not a direct substrate for LRRK2 kinase activity, following up on initial studies by Imai et al. (2008). They confirmed ...