LRRK2 overactive in idiopathic Parkinson's

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

Roberto Di Maio, J. Timothy Greenamyre (senior author) and colleagues (University of Pittsburgh, with Dario Alessi), Science Translational Medicine 10(451):eaar5429, 2018. Europe PMC lists support from the Michael J. Fox Foundation, the US NIH, the American Parkinson Disease Association and the UK Medical Research Council. The paper discloses that Greenamyre briefly held an advisory post at Pfizer.

What happened

The team built two new "proximity ligation" assays that light up phosphorylation of LRRK2 at Ser1292 and loss of 14-3-3 proteins from LRRK2. In postmortem substantia nigra from 7 people with idiopathic (no known cause) Parkinson's and 8 matched controls, and in two rat models, wild-type LRRK2 kinase activity was selectively raised in dopamine neurons: about 6-fold for Ser1292 phosphorylation and 4-fold for phosphorylated Rab10. The cause was oxidative (oxidising chemistry). It led to phosphorylation of Rab10 (landmark 37) and to faults in mitochondrial protein import and in lysosome function. The authors concluded that LRRK2 inhibitors may be useful in patients without LRRK2 mutations.

Why it moved us toward a cure

It was the stated reason to test a LRRK2 inhibitor in the general Parkinson's population rather than only in carriers, as in LUMA (landmark 145). That trial's failure means the link between raised LRRK2 activity and slowing is unproven. Landmark 145 should list this as a parent.

Outcome

Open, with a setback. The post mortem comparison is small (7 cases, 8 controls), the measurement has not been shown to predict a drug benefit, and one literature search found no independent confirmation of the Ser1292 assay in idiopathic disease. No correction or retraction was found. Also, in LUMA a spinal-fluid LRRK2 marker fell by only about 30%, so the brain target may not have been hit well.

Sources

• Di Maio et al., Sci Transl Med 2018;10(451):eaar5429, DOI 10.1126/scitranslmed.aar5429, PMID 30045977, PMC6344941 (abstract and results text read via Europe PMC and PubMed)
• Landmark 145 for LUMA outcomes
• Not yet verified: independent reproduction by other groups (one search found none); that the assay is reliable in blood or spinal fluid.