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We performed targeted mass spectrometry with an established protein panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) of drug-na\u00efve de novo PD, and sex-\/age-matched healthy controls (HC) cross-sectionally (88 PD, 46 HC) and longitudinally (104 PD, 58 HC) over 10 years. Multiple markers of autophagy, synaptic plasticity, and secretory pathways were reduced in PD. We added samples from prodromal subjects (9 cross-sectional, 12 longitudinal) with isolated REM sleep behavior disorder, revealing secretogranin-2 already decreased compared to controls. Machine learning identified neuronal pentraxin receptor and neurosecretory protein VGF as most relevant for discriminating between groups. CSF levels of LAMP2, neuronal pentraxins, and syntaxins in PD correlated with clinical progression, showing predictive potential for motor- and non-motor symptoms as a valid basis for future drug trials.<\/jats:p>","DOI":"10.1038\/s41531-024-00714-1","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T11:02:24Z","timestamp":1715943744000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid of de novo Parkinson\u2019s disease"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7752-2443","authenticated-orcid":false,"given":"Michael","family":"Bartl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Dakna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5713-2141","authenticated-orcid":false,"given":"Sandrina","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6316-6804","authenticated-orcid":false,"given":"Sebastian","family":"Schade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7892-8621","authenticated-orcid":false,"given":"Mary","family":"Xylaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e1rbara","family":"Fernandes Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Ernst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Lucia","family":"Muntean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Sixel-D\u00f6ring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Trenkwalder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Brinkmalm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brit","family":"Mollenhauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"key":"714_CR1","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1002\/mds.27806","volume":"34","author":"B Mollenhauer","year":"2019","unstructured":"Mollenhauer, B. et al. 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C.T. has received honoraria for consultancy from Roche, and honoraria for educational lectures from UCB, and has received research funding for the PPMI study from Michael J. Fox Foundation and funding from the EU (Horizon 2020) and stipends from the (International Parkinson\u2019s and Movement DisorderSociety) IPMDS. B.M. has received honoraria for consultancy from Roche, Biogen, AbbVie, UCB, and Sun Pharma Advanced Research Company. BM is a member of the executive steering committee of the Parkinson Progression Marker Initiative and PI of the Systemic Synuclein Sampling Study of the Michael J. Fox Foundation for Parkinson\u2019s Research and has received research funding from the Deutsche Forschungsgemeinschaft (DFG), EU (Horizon 2020), Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, Parkinson\u2019s Foundation and the Michael J. Fox Foundation for Parkinson\u2019s Research. M.L.M. has received honoraria for speaking engagements from Deutsche Parkinson Gesellschaft e.V. and royalties from Gesellschaft fur Medien + Kommunikation mbH + Co. FSD has received honoraria for speaking engagements from AbbVie, Bial, Ever Pharma, Medtronic and royalties from Elsevier and Springer. She served on an advisory board for Zambon and Stada Pharma. F.S.D. participated in Ad Boards for consultation: Abbvie, UCB, Bial, Ono, Roche and got honorary for lecturing: Stada Pharm, Abbvie, Alexion, Bial. S.S. received institutional salaries supported by the EU Horizon 2020 research and innovation program under grant agreement No. 863664 and by the Michael J. Fox Foundation for Parkinson\u2019s Research under grant agreement No. MJFF-021923. He is supported by a PPMI Early Stage Investigators Funding Program fellowship of the Michael J. Fox Foundation for Parkinson\u2019s Research under grant agreement No. MJFF-022656. H.Z. has served at scientific advisory boards and\/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). M.D., M.X., S.W., M.E., A.B., J.N., B.G. have no competing interests to report.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"102"}}