Objective: To compare Glucocerebrosidase-1 (GCase) activity in human monocytes of manifesting LRRK2 G2385R, R1628P, and double-variant carriers vs. idiopathic Parkinson’s disease (iPD) and healthy controls (HC).

Background: Pathogenic LRRK2 mutations increase kinase activity in Parkinson’s disease (PD), yet their role in disease pathogenesis remains unclear. Emerging evidence suggests a link between LRRK2 hyperactivation, lysosomal dysfunction and lysosomal GCase, encoded by GBA1, another major genetic risk factor for PD. While reduced GCase activity has been reported in PD patients with GBA1 mutations, its activity level in LRRK2-PD remains unclear. Previous studies have examined GCase activity in LRRK2 G2019S, R1441G, R1441C and M1646T carriers [1-3], but G2385R and R1628P variants, which each affects 5–10% of Asian PD populations [4], have not been studied.

Method: This case-control study included 243 subjects: manifesting carriers (PD-G2385R [n=57], PD-R1628P [n=61], PD-G2385R+R1628P [n=5]), as well as iPD (n=62) and HC (n=58) negative for G2385R and R1628P. GCase activity was measured in monocytes isolated from fresh blood by incubating lysates with the fluorescent substrate 4-methylumbelliferyl-β-D-glucopyranoside (4-MUG), followed by fluorescence quantification of the released 4-methylumbelliferone product [5].

Results: GCase activity was numerically higher in PD-R1628P, PD-G2385R and double-variant carriers compared to HC and iPD, but these differences were not statistically significant (Fig. 1). Substantial inter-individual variability in GCase activity was observed, with 37.1% iPD, 56.1% PD-G2385R, 59.0% PD-R1628P, and 60.0% double-variant carriers exhibiting GCase activity exceeding the median value for HC. Interestingly, higher GCase activity correlated significantly with increased Rab10 phosphorylation (a marker of LRRK2 kinase activity; r=0.390, adjusted p<0.001; Fig. 2) in the overall PD group.

Conclusion: Although GCase activity did not significantly differ between LRRK2-PD, HC and iPD, we note a significant correlation between higher GCase activity and increased LRRK2 kinase activity in the overall PD group. It will be important to further investigate the link between lysosomal dysfunction, GCase activity and LRRK2 signalling in PD pathogenesis by deploying lysosome specific probes for measuring GCase in combination with unbiased lysosomal profiling [6].

Fig. 1

Fig. 2

References: [1] Ysselstein D, Nguyen M, Young TJ, Severino A, Schwake M, Merchant K, Krainc D. LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients. Nature Communications. 2019;10(1):5570.
[2] Alcalay RN, Levy OA, Waters CH, Fahn S, Ford B, Kuo SH, Mazzoni P, Pauciulo MW, Nichols WC, Gan-Or Z, Rouleau GA. Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain. 2015;138(9):2648-58.
[3] Sosero YL, Yu E, Krohn L, Rudakou U, Mufti K, Ruskey JA, Asayesh F, Laurent SB, Spiegelman D, Fahn S, Waters C. LRRK2 p. M1646T is associated with glucocerebrosidase activity and with Parkinson’s disease. Neurobiology of Aging. 2021 Jul 1;103:142-e1.
[4] Lim SY, Tan AH, Ahmad-Annuar A, Okubadejo NU, Lohmann K, Morris HR, Toh TS, Tay YW, Lange LM, Bandres-Ciga S, Mata I. Uncovering the genetic basis of Parkinson’s disease globally: from discoveries to the clinic. The Lancet Neurology. 2024;23(12):1267-80.
[5] Saarela D, Lis P, Gomes S, Nirujogi RS, Dong W, Rawat E, Glendinning S, Zeneviciute K, Bagnoli E, Fasimoye R, Lin C. Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples. The Journal of Clinical Investigation. 2025;135(4).
[6] Zhu S, Deen MC, Zhu Y, Gilormini PA, Chen X, Davis OB, Chin MY, Henry AG, Vocadlo DJ. A Fixable Fluorescence‐Quenched Substrate for Quantitation of Lysosomal Glucocerebrosidase Activity in Both Live and Fixed Cells. Angewandte Chemie. 2023;135(40):e202309306.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/interrogating-gcase-activity-in-human-monocytes-isolated-from-parkinsons-disease-patients-carrying-the-asian-lrrk2-g2385r-and-r1628p-variants/