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Genetic mutations in GBA, encoding glucocerebrosidase, are key risk factors linked to lysosomal dysfunction, pathological α-synuclein accumulation, and major lipid changes. Ambroxol, a small-molecule chaperone stabilizing glucocerebrosidase, reverses lipid-level alterations and increases α-synuclein levels in GBA-related contexts. This work shows Ambroxol also directly inhibits α-synuclein–lipid coaggregation by blocking primary nucleation, including displacement from negatively charged membranes.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/ambroxol-displaces-alpha-synuclein-from-the-membrane-and-inhibits-the-formation-of-early-protein-lipid-coaggregates-research-paper/445457/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/ambroxol-displaces-alpha-synuclein-from-the-membrane-and-inhibits-the-formation-of-early-protein-lipid-coaggregates-research-paper/445457.png","ImageObject",300,407,{"name":92,"@type":93},"Logic","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is Parkinson’s disease in this study’s context?","Question",{"text":112,"@type":113},"Parkinson’s disease is described as a neurodegenerative disorder with neuronal loss and brain deposition of α-synuclein–lipid coaggregates, accompanied by disruptions in lipid metabolism.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does Ambroxol relate to GBA and glucocerebrosidase?",{"text":117,"@type":113},"Ambroxol is presented as a small-molecule chaperone that binds and stabilizes glucocerebrosidase, helping revert lipid-level changes linked to GBA mutations and affecting α-synuclein levels.",{"name":119,"@type":110,"acceptedAnswer":120},"What direct effect does Ambroxol have on α-synuclein–lipid coaggregation?",{"text":121,"@type":113},"The study reports that Ambroxol inhibits the primary nucleation step of the aggregation process, displacing α-synuclein from negatively charged membranes and preventing early α-synuclein–lipid coaggregate formation.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},445457,1791075684,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":52,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144,"preview_page_count":4},1099513958762,"https://ap-avatar.wpscdn.com/avatar/1000023916a998db790?x-image-process=image/resize,m_fixed,w_180,h_180&k=1784791008015729253","Chemical Science  \nEDGE ARTICLE  \nCite this: DOI: 10 .1039/d5sc06116d  \nAll publication charges for this article have been paid for by the Royal Society of Chemistry  \nReceived 12th August 2025  \nAccepted 28th October 2025 DOI: 10.1039/d5sc06116d[rsc.li/chemical-science](rsc.li/chemical-science)  \nAmbroxol displaces a-synuclein from the membrane and inhibits the formation of early protein–lipid coaggregates  \nJesper E. Dreier,a Alisdair Stevenson,bc Elliot Carles,a Katharina Schott,a Thomas C. T. Michaels  *bc and Cline Galvagnion  *a  \nParkinson's disease (PD) is a neurological disorder characterized by neuronal loss and the deposition of asynuclein–lipid coaggregates in the brain of patients as well as disruptions in lipid metabolism. Mutations in the gene GBA, which encodes the lysosomal glycoprotein Glucocerebrosidase, are together the most important genetic risk factor for PD and have been associated with lysosomal dysfunction, accumulation of pathological a-synuclein as well as major changes in both the levels and properties of lipids. Ambroxol, a small molecule chaperone capable of binding and stabilizing Glucocerebrosidase, was found to revert changes in lipid levels and increase in a-synuclein levels due to GBA mutations potentially via restoring lysosomal function. Here, we show that Ambroxol also has a direct effect on asynuclein–lipid coaggregation by inhibiting the primary nucleation step in the aggregation process. We find that Ambroxol not only displaces a-synuclein from negatively charged membranes but also prevents the formation of early a-synuclein–lipid coaggregates during primary nucleation. These results suggest that Ambroxol may have beneficial effects on other synucleinopathies, such as multiple system atrophy and dementia with Lewy Bodies, that are also characterised by the aggregation of a-synuclein into amyloid fibrils.  \n1 Introduction  \nParkinson's disease (PD) is the second most common neurodegenerative disease, second only to Alzheimer's disease and is characterized by the loss of dopaminergic neurons which leads to bradykinesia, tremors and dementia.1,2 Another hallmark of PD is the formation of protein–lipid inclusions in the brain called Lewy bodies, whose main protein constituent is a-synuclein (aS) .3,4  \naS is a small (14 kDa) intrinsically disordered protein (IDP) that is found at micro-molar concentrations in neuronal synapses,5 where its natural function is proposed to be involved in the budding and merging of synaptic vesicles.6 In Lewy bodies, however, aS is not found in a disordered state, but as rigid amyloid 􀀁brils, where aS monomers aggregate through bsheet stacking. Multiple factors have been shown to in􀀃uence the propensity of aS to form amyloid 􀀁brils in vitro, such as pH, temperature, metal ions and surfaces such as air/water, polystyrene/water,7 membrane/water8 or detergent/water9 interfaces.  \naDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark. E-mail: celine. [galvagnion@sund.ku.dk](galvagnion@sund.ku.dk)  \nbDepartment of Biology, Institute of Biochemistry, ETH Zurich, Otto Stern Weg 3, 8093 Zurich, Switzerland. E-mail: thomas.michaels@bc.biol.ethz.ch  \ncBringing Materials to Life (BML) Initiative, ETH Zurich, Switzerland  \nIn particular, the interaction between aS and lipid membranes has been shown to play a dual opposite role by being crucial for the proposed biological function of the protein, i.e. synaptic plasticity, while being required for the initiation of the formation of lipid–protein coaggregates.6,8,10 The molecular events responsible for the switch from functional to deleterious aSmembrane interactions are not yet fully understood. It is now well established that aS can bind to membranes made of different lipids, including negatively charged phospholipids, gangliosides and cardiolipin,11–13 but is only able to coaggregate with some of these lipids into lipid–protein amyloid 􀀁brils at h","cbCain2U24qYN5gU","https://ap.wps.com/l/cbCain2U24qYN5gU","pdf",3143720,"English","# Introduction\n## Parkinson’s disease, α-synuclein, and Lewy bodies\n## α-Synuclein aggregation and membrane influences\n## GBA mutations and lysosomal dysfunction\n## Ambroxol and its proposed chaperone role","[{\"question\":\"What is Parkinson’s disease in this study’s context?\",\"answer\":\"Parkinson’s disease is described as a neurodegenerative disorder with neuronal loss and brain deposition of α-synuclein–lipid coaggregates, accompanied by disruptions in lipid metabolism.\"},{\"question\":\"How does Ambroxol relate to GBA and glucocerebrosidase?\",\"answer\":\"Ambroxol is presented as a small-molecule chaperone that binds and stabilizes glucocerebrosidase, helping revert lipid-level changes linked to GBA mutations and affecting α-synuclein levels.\"},{\"question\":\"What direct effect does Ambroxol have on α-synuclein–lipid coaggregation?\",\"answer\":\"The study reports that Ambroxol inhibits the primary nucleation step of the aggregation process, displacing α-synuclein from negatively charged membranes and preventing early α-synuclein–lipid coaggregate formation.\"}]","Ambroxol displaces a-synuclein from the membrane and inhibits the formation of early protein–lipid coaggregates - Research paper | PDF",1790712161,25]