RAB29 recruits and activates LRRK2

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

MacLeod, Rhinn, Kuwahara and colleagues, with Abeliovich as last author (Neuron 77:425–439, 2013). Purlyte, Dhekne and colleagues, with Pfeffer and Alessi as last authors, a UK–US collaboration led from the MRC Protein Phosphorylation Unit in Dundee (EMBO J 37:1–18, 2018). Liu, West, Cookson and colleagues, with Cookson and West as last authors (Hum Mol Genet 27:385–395, 2018).

What happened

Genome-wide studies had flagged a region called PARK16 as a risk locus. One gene in it is RAB29, then called RAB7L1. RAB29 is a small protein that acts as a switch on cell membranes.

• 2013. MacLeod et al. found that the effects of variants at PARK16 and at LRRK2 on the brain's gene activity and on Parkinson's risk were closely related. Losing RAB7L1 in rodent neurons, or in fruit-fly dopamine neurons, reproduced the damage seen with mutant LRRK2. Adding extra RAB7L1 rescued it. Both defects disturbed protein sorting between the endosome (a sorting compartment), the lysosome and the Golgi, and lowered a protein called VPS35.
• 2018, Purlyte. RAB29 recruits LRRK2 to the trans-Golgi network and greatly stimulates its kinase activity. Mutant LRRK2 (R1441G/C and Y1699C) was recruited and activated more readily than normal LRRK2. In human A549 lung cells, knocking out RAB29 lowered LRRK2's phosphorylation of Rab10.
• 2018, Liu. Independent work found that LRRK2 mutations quadrupled its phosphorylation of RAB7L1 in cells, and that membrane-bound RAB7L1 activated LRRK2 and helped bring it to the Golgi.

Why it moved us toward a cure

LRRK2 had been shown to act by tagging Rab proteins (landmark 37). This work explained what switches it on, at which membrane, and tied the LRRK2 gene (landmark 7) to a second independent risk locus. It showed that a drug need not hit LRRK2's kinase directly. Blocking its activator or its recruitment is another route. Purlyte also suggested that RAB29 may control the blood-marker phosphorylation sites that drug trials use.

Outcome

Advanced. Most of the activation data are from cultured cells. How much RAB29 matters for LRRK2 activity in the human brain was not checked.

Sources

• MacLeod et al., Neuron 2013, DOI 10.1016/j.neuron.2012.11.033 (Europe PMC, PMID 23395371)
• Purlyte et al., EMBO J 2018, DOI 10.15252/embj.201798099 (PMC5753036)
• Liu et al., Hum Mol Genet 2018, DOI 10.1093/hmg/ddx410
• Corrections: Neuron issued two 2013 errata for MacLeod (6 Mar 2013, correcting an author's name, Neuron 77:994, DOI 10.1016/j.neuron.2013.02.021; and 10 Jul 2013, DOI 10.1016/j.neuron.2013.06.021, whose content was not read). EMBO J 2019;38:e101237 corrected Purlyte Figure 8A, where the Rab10 and Rab29 blot labels were swapped (PMC6331717). No retraction found. PubPeer could not be reached.
• Not yet verified: the PARK16 GWAS papers themselves; whether RAB29 is the causal gene at PARK16; the role of RAB29 in human brain, and later work that may have changed the picture; the full author lists.