LRRK2 and lysosome damage

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

Tomoya Eguchi, Tomoki Kuwahara, Takeshi Iwatsubo and colleagues (University of Tokyo, 2018); Susanne Herbst, Maximiliano Gutierrez, Nicholas Wood, Huw Morris and colleagues (Crick and UCL, 2020); Luis Bonet-Ponce, Mark Cookson (senior author, US National Institute on Aging) and colleagues (2020). Funders were not checked.

What happened

Lysosomes are the cell's recycling compartments. When they are damaged chemically, LRRK2 and its Rab substrates (landmark 37) are recruited to them in sequence, and Rab phosphorylation helps keep lysosomes in order (Eguchi, PNAS 115(39):E9115–E9124, Sept 2018; Rab7L1/Rab29 helps bring LRRK2 to the lysosome, and LRRK2-deficient mice showed more chloroquine-induced lysosomal damage in the kidney). In macrophages, activated LRRK2 brings Rab8A and a repair protein, CHMP4B, to damaged compartments; without LRRK2 and Rab8A they are cleared by lysophagy instead, and macrophages from Parkinson's patients with overactive LRRK2 mutations accumulated damaged endolysosomes (Herbst, EMBO J 39(18):e104494, 2020). In cultured cells exposed to LLOME, a lysosome-rupturing agent, LRRK2 phosphorylates RAB35 and RAB10, recruiting the adaptor JIP4 so that tubules bud from the lysosome and release their contents; the authors call this LYTL (Bonet-Ponce, Sci Adv 6(46):eabb2454, Nov 2020). A 2024 follow-up traced the recruiting route to the V-ATPase and ATG16L1 (Eguchi, J Cell Biol 223(3):e202302067).

Why it moved us toward a cure

It gave the LRRK2 pathway a plausible normal function, damage response, which connects LRRK2 (landmark 7, landmark 46) with the lysosomal genes GBA (landmark 16) and ATP13A2 (landmark 45). It also sharpens what an LRRK2 inhibitor might change.

Outcome

Open. The papers differ on what LRRK2 does (repair versus sorting), and the experiments were mostly in non-neuronal cells, with the patient data limited to macrophages, not dopamine neurons. The relation of this role to neuron loss remains unproven. No correction or retraction was found for the four papers. See the index for trial results on LRRK2 inhibition.

Sources

• Eguchi et al., PNAS 2018;115:E9115–E9124, DOI 10.1073/pnas.1812196115, PMID 30209220
• Herbst et al., EMBO J 2020;39:e104494, DOI 10.15252/embj.2020104494 (Crick)
• Bonet-Ponce et al., "LRRK2 mediates tubulation and vesicle sorting from lysosomes," Sci Adv 2020;6(46):eabb2454, DOI 10.1126/sciadv.abb2454, PMID 33177079 (abstract via Europe PMC)
• Eguchi et al., J Cell Biol 2024;223(3):e202302067, DOI 10.1083/jcb.202302067, PMID 38227290
• Not yet verified: whether LRRK2 behaves this way in human dopamine neurons; the earlier version's claim that the G2019S mutation raised tubulation about threefold (removed; not in the abstract); the Herbst and Bonet-Ponce funders.