A NAPE-LRRK2 metabolic axis controls lysosomal homeostasis in Parkinson's disease
Palese, F.; Giachino, C.; Syan, S.; Ottonello, G.; Sciandrone, G.; Filipponi, C.; Lai, M.; Armirotti, A.; Deleidi, M.; Zurzolo, C.
Show abstract
N-acylphosphatidylethanolamines (NAPEs) are atypical glycerophospholipids that accumulate in response to cellular stress, yet their roles beyond serving as precursors of fatty-acid ethanolamines (FAEs) remain largely unexplored. Here, we identify NAPEs as endogenous regulators of leucine-rich repeat kinase 2 (LRRK2), a master controller of lysosomal homeostasis and a genetic driver of Parkinsons disease. We show that increasing NAPE synthesis or blocking their hydrolysis inhibits LRRK2 kinase activity, enhances lysosomal function, and promotes the clearance of a-synuclein aggregates. Conversely, cells in which NAPE hydrolysis is enhanced display increased LRRK2 activation and lysosomal dysfunction. Importantly, in induced pluripotent stem cell-derived dopaminergic neurons carrying the LRRK2-G2019S variant, pharmacological inhibition of NAPE-PLD - the enzyme that degrades NAPEs - restores lysosomal activity and favors the clearance of preformed a-synuclein fibrils. Together, our findings identify NAPEs as previously unrecognized lipid regulators of LRRK2 signaling and lysosomal function, revealing a metabolic axis with therapeutic potential in Parkinsons disease.
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