PPM1H reverses LRRK2's Rab tags

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

Kerryn Berndsen (first author), Pawel Lis, Francesca Tonelli, Suzanne Pfeffer, Dario Alessi and colleagues. eLife 8:e50416, 30 Oct 2019. Listed funders include the Michael J. Fox Foundation (including a Langston Award), the UK Medical Research Council and the US NIH.

What happened

LRRK2 tags Rab proteins (landmark 37). The team screened all human protein phosphatases and found PPM1H counteracts it by dephosphorylating those Rabs. Knocking out PPM1H raised Rab phosphorylation in human A549 cells and slowed dephosphorylation; extra PPM1H lowered LRRK2-driven Rab phosphorylation. It directly dephosphorylated Rab8A in a test tube. A "substrate-trapping" mutant (Asp288Ala) held on to phosphorylated Rabs and blocked their loss after LRRK2 inhibitors. PPM1H sits at the Golgi, and its knockdown reduced primary cilia (a sensing antenna on cells), as pathogenic LRRK2 does. The closely related PPM1M also lowered Rab10 and Rab8A phosphorylation in cells, but less than PPM1H, and PPM1J did not.

Why it moved us toward a cure

LRRK2 drugs lower the kinase's activity. This showed the other half of the circuit: tag removal is its own enzyme, and the authors proposed that PPM1H enhancers could be a new treatment. Follow-up work: the crystal structure of PPM1H and the way it recognises phosphorylated Rabs (Waschbüsch et al., EMBO Rep 2021), and PPM1M as a phosphoRab12-preferring phosphatase, with a rare inactive variant found in people with Parkinson's (Chiang et al., Cell Rep 2025).

Outcome

Advanced as mechanism: it was built on by structural and genetic follow-ups. Whether raising PPM1H activity helps people is untested; no PPM1H-activating drug appears in the sources read.

Sources

• Berndsen et al., eLife 2019;8:e50416, DOI 10.7554/eLife.50416, PMID 31663853 (abstract and full text via Europe PMC, PMC6850886)
• Waschbüsch et al., EMBO Rep 2021, DOI 10.15252/embr.202152675
• Chiang et al., Cell Rep 2025, DOI 10.1016/j.celrep.2025.116031
• Not yet verified: the authors' institutions and who was senior author (inferred from the author order and grants); whether any company is developing a PPM1H activator; the full eLife methods.