LRRK2 phosphorylates Rab proteins

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

Martin Steger, Francesca Tonelli, Dario Alessi (University of Dundee, MRC Protein Phosphorylation and Ubiquitylation Unit), Matthias Mann (Max Planck Institute of Biochemistry) and 13 colleagues (17 authors in all, including Marco Baptista of the Michael J. Fox Foundation). Funders not recorded here.

What happened

LRRK2 (landmark 7) is a kinase, an enzyme that attaches phosphate tags to other proteins. The common G2019S mutation raises its activity two- to threefold. For over a decade nobody agreed what it tagged, which made drug development hard. Using phosphoproteomics (measuring thousands of tags at once), genetics and inhibitor drugs, the team found that LRRK2 directly phosphorylates a subset of Rab GTPases at one conserved spot, both in cells and in a test tube. Disease-causing LRRK2 variants from different parts of the protein all increased the tagging, which weakened the Rabs' binding to partner proteins. The paper, "Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases", appeared in eLife 5:e12813 on 29 January 2016.

Why it moved us toward a cure

It gave the field a measurable readout. In 2018, VPS35 D620N (landmark 36) was shown to raise LRRK2 phosphorylation of Rab8A, Rab10 and Rab12. Denali reported in 2021 that its LRRK2 inhibitor lowered phospho-Rab10 by roughly 50% or more at all doses in patients, and that, adjusted for total LRRK2, patients and LRRK2 carriers had about double the level of healthy volunteers. In the 648-person LUMA trial (announced 21 May 2026), the companies reported peripheral LRRK2 kinase inhibition above 90% and up to about a 30% fall in phospho-Rab10 in a spinal-fluid sub-study.

Outcome

Advanced as understanding. The pathway is validated, but the drug test was not: BIIB122 hit its target yet did not slow progression in early Parkinson's (dead ends). Whether blocking the pathway helps mutation carriers is being tested in BEACON.

Sources

• Steger et al., eLife 2016;5:e12813, DOI 10.7554/eLife.12813, PMID 26824392 (abstract and author list read via Europe PMC and Crossref) · MRC PPU record · DOAJ abstract, Jan 2016
• Mir et al., Biochem J 2018;475:1861–1883, DOI 10.1042/BCJ20180248 (abstract read via Europe PMC)
• Denali phase 1/1b release, May 2021
• Biogen and Denali release on LUMA, 21 May 2026 (read as a search summary) · Clinical Trial Vanguard, 24 May 2026 (secondary report)
• No correction or retraction found for the eLife paper; it has two linked comments (Europe PMC, 20 Oct 2026).
• Not yet verified: the eLife full text (abstract only); which Rabs and how many Steger found (the 2018 follow-up names Rab8A, Rab10, Rab12); the LUMA release itself (search summary only); the institutions of the other authors.