PIKfyve inhibition induces LRRK2 activation through phosphatidylinositol 3-phosphate and CASM

In cells, blocking PIKfyve elevates PI3P and triggers LRRK2 hyperactivation, while adding class III PI3K inhibition suppresses that activation.

• Why it matters: LRRK2 hyperactivation linked to Parkinson’s disease is known to occur on stressed endolysosomal membranes via CASM and Rab, but the specific lipid requirement was unclear.
• What they did: The study used PIKfyve inhibition and additional class III PI3K inhibition, measured PI3P during LRRK2 activation, tested effects of PI3K inhibitors on CASM-induced activation, and performed co-localization and in vitro PI3P binding assays.
• The result: LRRK2 activation required CASM, Rab, and PI3P-rich LAMP1-positive enlarged vacuoles, and LRRK2 directly bound PI3P via N-terminal positively charged amino acids, supporting a combined membrane-lipid mechanism.

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