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Defective glycosphingolipid transport and degradation\u2014especially via the lipid-degrading enzyme glucocerebrosidase 1 (GCase, gene\n                    <jats:italic>GBA1<\/jats:italic>\n                    )\u2014aggravate PD and increase dementia risk. Ambroxol is a mucolytic drug and has emerged as a promising add-on therapy for PD since it acts as a chaperone for misfolded GCase, thereby increases the likelihood that mutated and misfolded GCase eludes ER-associated degradation (ERAD) and is transported to its destination, the lysosome. In this study we investigated whether and how ambroxol provided therapeutic benefits for PD irrespective of the GBA1 mutation status. Pink1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \/SNCA\n                    <jats:sup>A53T<\/jats:sup>\n                    double mutant PD mice were administered ambroxol either via the drinking water (120\u2013150\u2009mg\u00b7kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7d\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) or via food pellets (75\u2013100\u2009mg\u00b7kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7d\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) for approximately 6 months. During the treatments mice were observed in IntelliCages; and in motor, sensory and cognitive functions tests. After mice were euthanized, tissues were dissected for protein, lipidomic and metabolomic analyses. We showed that high-dose long-term ambroxol was well tolerated and led to mild behavioral and metabolic improvements but had adverse effects on brain sulfatides, lysosomal functions and mitochondrial cardiolipins. Notably, brain levels of glucosylceramides (GlcCer 16:0) were normalized, while sulfatides (SHexCer) further increased. Western blots revealed a modest reduction of \u03b1Syn and phosphorylated \u03b1Syn (P-Ser129). IntelliCage assessments showed increased exploratory activity with ambroxol, suggesting reduced bradykinesia, though sensory and motor functions remained unchanged. Lipidomic profiles of mitochondria showed accumulation of HexCer and triglycerides in PD mitochondria, regardless of treatment, while ambroxol led to an additional decline of cardiolipins including the most abundant tetralinoleoyl cardiolipins. In HT22 hippocampal neurons preloaded with \u03b1Syn pre-formed fibrils, ambroxol accumulated within lysosomes, increased lysosomal mass and sphingolipid content and promoted lysosomal enzyme release. Collectively, these results suggest that ambroxol confers transient behavioral benefits and modestly reduces \u03b1Syn pathology, albeit with potential drawbacks. In addition, its lysosomal accumulation may further disrupt sphingolipid metabolism and impair mitochondrial compensatory mechanisms. Ambroxol-induced lysosomal exocytosis may transiently relieve \u03b1Syn burden, but further interventions would be required to ensure \u03b1Syn clearance from the brain.\n                  <\/jats:p>","DOI":"10.1038\/s41401-025-01690-9","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T10:55:07Z","timestamp":1765191307000},"page":"836-859","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Modest improvement of metabolic and behavioral deficits with long-term ambroxol treatment in a Pink1\u2212\/\u2212SNCAA53T double mutant mouse model of Parkinson\u2019s disease"],"prefix":"10.1038","volume":"47","author":[{"given":"Luisa","family":"Franck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Valek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Hahnefeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Trautmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Angioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-Philipp","family":"Weyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Gurke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilka","family":"Wittig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd","family":"Geisslinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irmgard","family":"Tegeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"1690_CR1","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","volume":"386","author":"LV Kalia","year":"2015","unstructured":"Kalia LV, Lang AE. 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The maintenance of the breeding colony of\n                      Pink1\n                      \n                        \u2212\/\u2212\n                      \n                      SNCA\n                      A53T\n                      mice and observation up to onset of PD symptoms were approved under FK1032 (12.02.205-11.02.2020) and FK1131 (17.02.2020-31.12.2023). For primary cultures and tissue analyses of wild type mice, tissue was obtained after euthanization according to $4 of the German Tierschutzgesetz in compliance with the ARRIVE principles [\n                      \n                      ], and with European guidelines and GV-SOLAS recommendations for animal welfare in science.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}