LRRK2 lowers GCase

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

Daniel Ysselstein, Dimitri Krainc and colleagues (Northwestern University Feinberg School of Medicine), Nature Communications 2019. Funders listed include the US NIH (NINDS) and the Michael J. Fox Foundation. Krainc declares advisory roles with Prevail Therapeutics and Intellia and is a venture partner at Orbimed.

What happened

The team grew dopamine neurons from stem cells made from patients with LRRK2 mutations or GBA1 mutations.

• GCase activity was lower in neurons carrying LRRK2 mutations.
• The LRRK2 kinase inhibitor MLi-2 increased GCase activity in neurons with either LRRK2 or GBA1 mutations, restoring it to the level of gene-corrected control neurons in the LRRK2 lines.
• The increase was enough to partly rescue build-up of oxidised dopamine and alpha-synuclein.
• The LRRK2 substrate Rab10 (landmark 37) was identified as a key mediator.

Why it moved us toward a cure

LRRK2 (landmark 96) and GBA (landmark 16) had been treated as separate branches. This work says they may meet in the lysosome, so a LRRK2 inhibitor could in principle help GBA carriers too, and lysosome biomarkers could be shared.

Outcome

Open. It is cell-culture work on patient-derived neurons. The LRRK2 inhibitor BIIB122 did not slow broad early Parkinson's (landmark 145), and human data on GCase after LRRK2 inhibition were not checked.

Sources

• Ysselstein et al., Nat Commun 2019;10:5570, DOI 10.1038/s41467-019-13413-w
• Full text, PMC6895201
• Not yet verified: percentage change in GCase and number of lines per experiment; independent replication; effects in animals or people. I found no correction or retraction.