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bioRxiv · 10.1101/2025.10.10.681687

LRRK2 Kinase Mediates Increased GCase Activity in Microglia in Response to Proinflammatory Stimuli

MacDougall, E. J.·Chen, C. X.- Q.·Deneault, E.·You, Z.·Abdian, N.·Durcan, T. M.·Senkevich, K.·Gan-Or, Z.·Fon, E. A.
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Abstract

Variants in the LRRK2 and GBA1 genes are among the most common risk factors associated with Parkinsons disease (PD). Both patients carrying PD-associated variants in GBA1, encoding lysosomal enzyme glucocerebrosidase (GCase), and a subset of non-carrier patients have been shown to have reduced GCase enzymatic activity, suggesting that reduced GCase activity may be a feature of both genetic and a subset of sporadic PD. However, the effect of PD-associated variants in LRRK2, encoding a serine/threonine kinase, on GCase activity remains controversial, with conflicting results in various tissues and cell types. Moreover, rare patients carrying both GBA1 and LRRK2 risk alleles seem to have a more benign disease course than carriers of GBA1 variants alone, suggesting a complex interplay between these two genes in PD. Here we evaluate the effect of LRRK2 kinase activity on GCase activity in human induced pluripotent stem cell (iPSC)-derived microglia (iMGs), a PD-relevant brain cell type expressing high levels of LRRK2. Using CRISPR editing, isogenic control iPSC lines were generated to match PD patient-derived iPSC lines harbouring the LRRK2 p.G2019S, p.M1646T, or p.N551K-p.R1398H protective haplotype variants. Whereas iMGs harbouring the p.M1646T variant, and the protective haplotype, respectively increased and decreased phosphorylation of canonical LRRK2 substrate, Rab10, GCase protein levels and activity were not altered in any of the LRRK2 variant lines. Additionally, whereas pharmacological inhibition of LRRK2 kinase activity had no impact on GCase activity in iMGs under basal conditions, it attenuated the increase in GCase activity elicited in response to interferon {gamma} (IFN{gamma}) treatment. Moreover, GCase activity induced by IFN{gamma} was reduced in PD risk LRRK2 p.M1646T iMGs and increased in p.N551K-p.R1398H protective haplotype iMGs compared to their isogenic corrected controls, congruent with their respective effects on LRRK2 kinase activity and PD risk. Thus, our data suggests a role for LRRK2 kinase activity in regulation of GCase activity in response to neuroinflammation.

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MacDougall, E. J., Chen, C. X.- Q., Deneault, E., You, Z., Abdian, N., Durcan, T. M., Senkevich, K., Gan-Or, Z., Fon, E. A.. 2025-10-12. LRRK2 Kinase Mediates Increased GCase Activity in Microglia in Response to Proinflammatory Stimuli. https://doi.org/10.1101/2025.10.10.681687

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