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The potential use of LRRK2 inhibitors for treating not only LRRK2\u2010associated PD (LRRK2\u2010PD) but also GBA1\u2010associated PD (GBA1\u2010PD) is currently under discussion. In the present study, we aimed to evaluate whether LRRK2 inhibition affects lysosomal hydrolase enzymatic activities, autophagy, and alpha\u2010synuclein levels in various cell types derived from LRRK2\u2010PD and GBA1\u2010PD patients, including macrophages derived from peripheral blood mononuclear cells (PBMC\u2010derived macrophages), dopaminergic (DA) neurons derived from induced pluripotent stem cells (iPSC\u2010derived DA neurons), and SH\u2010SY5Y cells. We first characterized PBMC\u2010derived macrophages from patients with LRRK2\u2010PD. Confocal microscopy revealed reduced colocalization of GCase with the lysosomal marker LAMP2, indicating impaired lysosomal translocation of the enzyme. In parallel, we observed decreased activity of galactosylceramidase (GALC), increased levels of lysosphingolipids (HexSph, LysoGb3, LysoSM) as measured by LC\u2013MS\/MS, and decreased pro\u2010form of cathepsin D, as assessed by Western blot analysis, compared to controls. However, no significant differences in GCase activity and protein levels were observed in PBMC\u2010derived macrophages of LRRK2\u2010PD patients and controls. In subsequent experiments, we found that LRRK2 inhibition not only increased GCase activity in both PBMC\u2010derived macrophages and iPSC\u2010derived DA neurons but also augmented the activity of other lysosomal enzymes, including acid sphingomyelinase (ASMase), alpha\u2010galactosidase (GLA), and GALC. Notably, this enhancement was more pronounced in iPSC\u2010derived DA neurons compared to PBMC\u2010derived macrophages. Similar increases in lysosomal hydrolase activities (GCase, ASMase, GALC, and GLA) were also observed in the SH\u2010SY5Y neuroblastoma cell line after LRRK2 inhibition. Interestingly, LRRK2 inhibition was more effective in GBA1\u2010PD than in LRRK2\u2010PD. We demonstrated that LRRK2 inhibition enhances both the protein levels of GCase and its translocation to lysosomes. This study provides the first evidence that inhibition of LRRK2 activity may increase GCase level and its translocation to lysosomes, thereby ameliorating lysosomal function. Moreover, LRRK2 inhibition also enhances the activity of other lysosomal hydrolases. Our findings expand the understanding of the molecular mechanism of LRRK2 inhibitors, offering valuable insights for further development of PD treatments.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70214-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70214","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T11:46:01Z","timestamp":1756899961000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Restoration of Lysosomal Hydrolase Activities by\n                    <scp>LRRK2<\/scp>\n                    Inhibition in\n                    <i>GBA1<\/i>\n                    \u2010 and\n                    <i>LRRK2<\/i>\n                    \u2010Associated Parkinson's Disease Patient\u2010Derived Cells"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5132-2283","authenticated-orcid":false,"given":"T. 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Konstantinov of National Research Center \u201cKurchatov Institute\u201d  Gatchina Russian Federation"},{"name":"Pavlov First Saint\u2010Petersburg State Medical University  Saint Petersburg Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. V.","family":"Grigor'eva","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences  Novosibirsk Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. V.","family":"Pavlova","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences  Novosibirsk Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. V.","family":"Baydakova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics  Moscow Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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