{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T10:51:58Z","timestamp":1788000718404,"version":"build-2784847793"},"reference-count":103,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Parma","award":["1737591"],"award-info":[{"award-number":["1737591"]}]},{"name":"University of Parma","award":["2016-0428"],"award-info":[{"award-number":["2016-0428"]}]},{"name":"University of Parma","award":["MJFF-021665"],"award-info":[{"award-number":["MJFF-021665"]}]},{"name":"Regional Foundation for Biomedical Research","award":["1737591"],"award-info":[{"award-number":["1737591"]}]},{"name":"Regional Foundation for Biomedical Research","award":["2016-0428"],"award-info":[{"award-number":["2016-0428"]}]},{"name":"Regional Foundation for Biomedical Research","award":["MJFF-021665"],"award-info":[{"award-number":["MJFF-021665"]}]},{"name":"Cariplo Foundation","award":["1737591"],"award-info":[{"award-number":["1737591"]}]},{"name":"Cariplo Foundation","award":["2016-0428"],"award-info":[{"award-number":["2016-0428"]}]},{"name":"Cariplo Foundation","award":["MJFF-021665"],"award-info":[{"award-number":["MJFF-021665"]}]},{"name":"MJF Foundation","award":["1737591"],"award-info":[{"award-number":["1737591"]}]},{"name":"MJF Foundation","award":["2016-0428"],"award-info":[{"award-number":["2016-0428"]}]},{"name":"MJF Foundation","award":["MJFF-021665"],"award-info":[{"award-number":["MJFF-021665"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Clusterin (CLU) is a heterodimeric, ATP-independent molecular chaperone that exhibits high expression in the brain. While CLU primarily functions in the extracellular environment, its chaperone activity in the intracellular compartment under different stress conditions, as well as its involvement in various signaling networks, has been demonstrated. CLU has been extensively associated with Alzheimer\u2019s Disease; however, increasing evidence links this chaperone to Parkinson\u2019s Disease (PD) as well. Thus, in this review we will discuss evidence concerning the involvement of CLU in the pathogenesis of PD with a particular focus on molecular mechanisms leading to the formation and the spreading of alpha-Synuclein (\u03b1-Syn) aggregates. Specifically, the role of CLU will be discussed in neurons and in glial cells, taking into account that the neuron\u2013glia cross-talk is an essential and dynamic interplay that is compromised in neurodegenerative disorders. Moreover, the possible role of CLU as a biomarker in different biological fluids, such as cerebrospinal fluid, plasma, and serum, and its therapeutic potential will be addressed. In this regard, the past years have seen huge efforts to discover molecules able to mitigate \u03b1-Syn burden and its related toxicity. Overall, this overview highlights CLU as an intriguing target that can affect biochemical events underlying PD pathology.<\/jats:p>","DOI":"10.3390\/ijms26136351","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T09:29:01Z","timestamp":1751362141000},"page":"6351","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Emerging Role of the Molecular Chaperone Clusterin in Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8096-9417","authenticated-orcid":false,"given":"Giulia","family":"Carini","sequence":"first","affiliation":[{"name":"Unit of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Via Europa 11, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salihu","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-148X","authenticated-orcid":false,"given":"Alice","family":"Filippini","sequence":"additional","affiliation":[{"name":"Unit of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Via Europa 11, 25123 Brescia, Italy"},{"name":"IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Via Pilastroni 4, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1009-2917","authenticated-orcid":false,"given":"Ileana","family":"Ramazzina","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy"},{"name":"Centre for Molecular and Translational Oncology (COMT), University of Parma, Parco Area delle Scienze 11\/a, 43124 Parma, Italy"},{"name":"Biostructures and Biosystems National Institute (INBB), Viale Medaglie d\u2019Oro 305, 00136 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6151-2451","authenticated-orcid":false,"given":"Isabella","family":"Russo","sequence":"additional","affiliation":[{"name":"Unit of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Via Europa 11, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41392-025-02166-2","article-title":"Advances in the Structures, Mechanisms and Targeting of Molecular Chaperones","volume":"10","author":"Gu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.1002\/pro.4189","article-title":"Expanding the Family of Extracellular Chaperones: Identification of Human Plasma Proteins with Chaperone Activity","volume":"30","author":"Geraghty","year":"2021","journal-title":"Protein Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4750","DOI":"10.1007\/s12035-023-03846-2","article-title":"Molecular Chaperones as Therapeutic Target: Hallmark of Neurodegenerative Disorders","volume":"61","author":"Sharma","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00401-002-0546-4","article-title":"Clusterin\/Apolipoprotein J Is Associated with Cortical Lewy Bodies: Immunohistochemical Study in Cases with \u03b1-Synucleinopathies","volume":"104","author":"Sasaki","year":"2002","journal-title":"Acta Neuropathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e48255","DOI":"10.7554\/eLife.48255","article-title":"Brain Clusterin Protein Isoforms and Mitochondrial Localization","volume":"8","author":"Herring","year":"2019","journal-title":"eLife"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1093\/oxfordjournals.jbchem.a123938","article-title":"Identification of the Disulfide Bonds in Human Plasma Protein SP-40,40 (Apolipoprotein-J)","volume":"112","author":"Takahashi","year":"1992","journal-title":"J. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1002\/pro.5560061007","article-title":"Identification and Characterization of Glycosylation Sites in Human Serum Clusterin","volume":"6","author":"Kapron","year":"1997","journal-title":"Protein Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/bmc-2015-0026","article-title":"The CLU-Files: Disentanglement of a Mystery","volume":"7","author":"Rohne","year":"2016","journal-title":"Biomol. Concepts"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Satapathy, S., Dabbs, R.A., and Wilson, M.R. (2020). Rapid High-Yield Expression and Purification of Fully Post-Translationally Modified Recombinant Clusterin and Mutants. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-70990-3"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1159\/000366365","article-title":"The Chaperone Activity of Clusterin Is Dependent on Glycosylation and Redox Environment","volume":"34","author":"Rohne","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Prochnow, H., Gollan, R., Rohne, P., Hassemer, M., Koch-Brandt, C., and Baiersd\u00f6rfer, M. (2013). Non-Secreted Clusterin Isoforms Are Translated in Rare Amounts from Distinct Human MRNA Variants and Do Not Affect Bax-Mediated Apoptosis or the NF-\u039aB Signaling Pathway. PLoS ONE, 8.","DOI":"10.1371\/annotation\/48cea21c-d035-4757-bf42-c97028306f11"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11590","DOI":"10.1074\/jbc.M209233200","article-title":"Synthesis and Functional Analyses of Nuclear Clusterin, a Cell Death Protein","volume":"278","author":"Leskov","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Foster, E.M., Dangla-Valls, A., Lovestone, S., Ribe, E.M., and Buckley, N.J. (2019). Clusterin in Alzheimer\u2019s Disease: Mechanisms, Genetics, and Lessons from Other Pathologies. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00164"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1111\/j.1600-0854.2007.00549.x","article-title":"Stress-Induced Retrotranslocation of Clusterin\/ApoJ into the Cytosol","volume":"8","author":"Nizard","year":"2007","journal-title":"Traffic"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s40478-017-0481-1","article-title":"Clusterin Protects Neurons against Intracellular Proteotoxicity","volume":"5","author":"Gregory","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1038\/onc.2012.212","article-title":"GRP78 Regulates Clusterin Stability, Retrotranslocation and Mitochondrial Localization under ER Stress in Prostate Cancer","volume":"32","author":"Li","year":"2013","journal-title":"Oncogene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1111\/j.1432-1033.1994.tb18807.x","article-title":"Molecular Characterization of Human TRPM-2\/Clusterin, a Gene Associated with Sperm Maturation, Apoptosis and Neurodegeneration","volume":"221","author":"Wong","year":"1994","journal-title":"Eur. J. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1007\/s10815-012-9779-x","article-title":"Presence, Localization, and Origin of Clusterin in Normal Human Spermatozoa","volume":"29","author":"Han","year":"2012","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7657876","DOI":"10.1155\/2022\/7657876","article-title":"The Influence of Clusterin Glycosylation Variability on Selected Pathophysiological Processes in the Human Body","volume":"2022","author":"Janiszewska","year":"2022","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Janiszewska, E., Kokot, I., Gilowska, I., Faundez, R., and Kratz, E.M. (2021). The Possible Association of Clusterin Fucosylation Changes with Male Fertility Disorders. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-95288-w"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s40478-025-02015-x","article-title":"Astrocytes Carrying LRRK2 G2019S Exhibit Increased Levels of Clusterin Chaperone via MiR-22-5p and Reduced Ability to Take up \u03b1-Synuclein Fibrils","volume":"13","author":"Filippini","year":"2025","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1002\/glia.23920","article-title":"Extracellular Clusterin Limits the Uptake of \u03b1-Synuclein Fibrils by Murine and Human Astrocytes","volume":"69","author":"Filippini","year":"2021","journal-title":"Glia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1002\/cne.903390307","article-title":"Clusterin (SGP-2): A Multifunctional Glycoprotein with Regional Expression in Astrocytes and Neurons of the Adult Rat Brain","volume":"339","author":"Pasinetti","year":"1994","journal-title":"J. Comp. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1080\/10715760600902310","article-title":"Regulation of Clusterin\/Apolipoprotein J, a Functional Homologue to the Small Heat Shock Proteins, by Oxidative Stress in Ageing and Age-Related Diseases","volume":"40","author":"Trougakos","year":"2006","journal-title":"Free Radic. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7714","DOI":"10.1016\/S0021-9258(18)32238-5","article-title":"Purification and Characterization of a Cell-Aggregating Factor (Clusterin), the Major Glycoprotein in Ram Rete Testis Fluid","volume":"258","author":"Blaschuk","year":"1983","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Rivera, C., Garcia, M.M., Molina-\u00c1lvarez, M., Gonz\u00e1lez-Mart\u00edn, C., and Goicoechea, C. (2021). Clusterin: Always Protecting. Synthesis, Function and Potential Issues. Biomed. Pharmacother., 134.","DOI":"10.1016\/j.biopha.2020.111174"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Peix, L., Evans, I.C., Pearce, D.R., Simpson, J.K., Maher, T.M., and McAnulty, R.J. (2018). Diverse Functions of Clusterin Promote and Protect against the Development of Pulmonary Fibrosis. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-20316-1"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Flanagan, L., Whyte, L., Chatterjee, N., and Tenniswood, M. (2010). Effects of Clusterin Over-Expression on Metastatic Progression and Therapy in Breast Cancer. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-107"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yuste-Checa, P., Bracher, A., and Hartl, F.U. (2022). The Chaperone Clusterin in Neurodegeneration\u2212friend or Foe?. BioEssays, 44.","DOI":"10.1002\/bies.202100287"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15953","DOI":"10.1021\/bi002189x","article-title":"Clusterin Is an ATP\u2014Independent Chaperone with Very Broad Substrate Specificity that Stabilizes Stressed Proteins in a Folding-Competent State","volume":"39","author":"Poon","year":"2000","journal-title":"Biochemistry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.1007\/s00018-011-0684-8","article-title":"Clusterin Facilitates in Vivo Clearance of Extracellular Misfolded Proteins","volume":"68","author":"Wyatt","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s11302-015-9483-2","article-title":"Extracellular ATP and Other Nucleotides\u2014Ubiquitous Triggers of Intercellular Messenger Release","volume":"12","author":"Zimmermann","year":"2016","journal-title":"Purinergic Signal"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s Disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1002\/ana.26467","article-title":"Effect Modification between Genes and Environment and Parkinson\u2019s Disease Risk","volume":"92","author":"Brolin","year":"2022","journal-title":"Ann. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1007\/s00702-023-02635-4","article-title":"The Heterogeneity of Parkinson\u2019s Disease","volume":"130","author":"Borghammer","year":"2023","journal-title":"J. Neural Transm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s Disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Cuenca-Bermejo, L., Almela, P., Navarro-Zaragoza, J., Villalba, E.F., Gonz\u00e1lez-Cuello, A.M., Laorden, M.L., and Herrero, M.T. (2021). Cardiac Changes in Parkinson\u2019s Disease: Lessons from Clinical and Experimental Evidence. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413488"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.pneurobio.2015.07.003","article-title":"Protein Aggregation and Neurodegeneration in Prototypical Neurodegenerative Diseases: Examples of Amyloidopathies, Tauopathies and Synucleinopathies","volume":"155","author":"Bourdenx","year":"2017","journal-title":"Prog. Neurobiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Srinivasan, E., Chandrasekhar, G., Chandrasekar, P., Anbarasu, K., Vickram, A.S., Karunakaran, R., Rajasekaran, R., and Srikumar, P.S. (2021). Alpha-Synuclein Aggregation in Parkinson\u2019s Disease. Front. Med., 8.","DOI":"10.3389\/fmed.2021.736978"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/s41419-023-05672-9","article-title":"Alpha-Synuclein in Parkinson\u2019s Disease and Other Synucleinopathies: From Overt Neurodegeneration Back to Early Synaptic Dysfunction","volume":"14","author":"Calabresi","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1016\/j.celrep.2016.12.023","article-title":"Synucleins Have Multiple Effects on Presynaptic Architecture","volume":"18","author":"Vargas","year":"2017","journal-title":"Cell Rep."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gao, V., Briano, J.A., Komer, L.E., and Burr\u00e9, J. (2023). Functional and Pathological Effects of \u03b1-Synuclein on Synaptic SNARE Complexes. J. Mol. Biol., 435.","DOI":"10.1016\/j.jmb.2022.167714"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"10510","DOI":"10.1523\/JNEUROSCI.1659-16.2016","article-title":"Monomeric Alpha-Synuclein Exerts a Physiological Role on Brain ATP Synthase","volume":"36","author":"Ludtmann","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Thorne, N.J., and Tumbarello, D.A. (2022). The Relationship of Alpha-Synuclein to Mitochondrial Dynamics and Quality Control. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.947191"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1021\/acs.nanolett.8b02916","article-title":"Mapping Surface Hydrophobicity of \u03b1-Synuclein Oligomers at the Nanoscale","volume":"18","author":"Lee","year":"2018","journal-title":"Nano Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8637","DOI":"10.1073\/pnas.0712179105","article-title":"The Fold of \u03b1-Synuclein Fibrils","volume":"105","author":"Vilar","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-94-007-5416-4_6","article-title":"\u03b1-Synuclein Aggregation and Modulating Factors","volume":"65","author":"Paleologou","year":"2012","journal-title":"Subcell. Biochem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Won, S.J., Fong, R., Butler, N., Sanchez, J., Zhang, Y., Wong, C., Tambou Nzoutchoum, O., Huynh, A., Pan, J., and Swanson, R.A. (2022). Neuronal Oxidative Stress Promotes \u03b1-Synuclein Aggregation In Vivo. Antioxidants, 11.","DOI":"10.3390\/antiox11122466"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s10571-019-00649-9","article-title":"\u03b1-Synuclein and Glia in Parkinson\u2019s Disease: A Beneficial or a Detrimental Duet for the Endo-Lysosomal System?","volume":"39","author":"Filippini","year":"2019","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/1742-2094-11-52","article-title":"LRRK2 and Neuroinflammation: Partners in Crime in Parkinson\u2019s Disease?","volume":"11","author":"Russo","year":"2014","journal-title":"J. Neuroinflammation"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.nrl.2021.10.003","article-title":"Relationship between Inflammation and Oxidative Stress and Its Effect on Multiple Sclerosis","volume":"39","author":"Ortiz","year":"2024","journal-title":"Neurolog\u00eda"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s12035-012-8267-8","article-title":"Inflammation and \u03b1-Synuclein\u2019s Prion-like Behavior in Parkinson\u2019s Disease\u2014Is There a Link?","volume":"47","author":"Tyson","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/s12276-022-00789-x","article-title":"TNF-\u03b1 Promotes \u03b1-Synuclein Propagation through Stimulation of Senescence-Associated Lysosomal Exocytosis","volume":"54","author":"Bae","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1038\/s12276-022-00895-w","article-title":"Inflammation Promotes Synucleinopathy Propagation","volume":"54","author":"Kim","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"103931","DOI":"10.1016\/j.mcn.2024.103931","article-title":"Systemic Inflammation Activates Coagulation and Immune Cell Infiltration Pathways in Brains with Propagating \u03b1-Synuclein Fibril Aggregates","volume":"129","author":"Laursen","year":"2024","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1046\/j.1471-4159.2002.01190.x","article-title":"TorsinA and Heat Shock Proteins Act as Molecular Chaperones: Suppression of \u03b1-Synuclein Aggregation","volume":"83","author":"McLean","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Mohammed, S., Russo, I., and Ramazzina, I. (2023). Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of \u03b1-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson\u2019s Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713370"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Cardinale, A., Calabrese, V., de Iure, A., and Picconi, B. (2021). Alpha-Synuclein as a Prominent Actor in the Inflammatory Synaptopathy of Parkinson\u2019s Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126517"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Hu, S., Tan, J., Qin, L., Lv, L., Yan, W., Zhang, H., Tang, B.S., and Wang, C. (2021). Molecular Chaperones and Parkinson\u2019s Disease. Neurobiol. Dis., 160.","DOI":"10.1016\/j.nbd.2021.105527"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"39155","DOI":"10.1074\/jbc.M405456200","article-title":"Analysis of \u03b1-Synuclein-Associated Proteins by Quantitative Proteomics","volume":"279","author":"Zhou","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Lenzi, C., Ramazzina, I., Russo, I., Filippini, A., Bettuzzi, S., and Rizzi, F. (2020). The Down-Regulation of Clusterin Expression Enhances the Asynuclein Aggregation Process. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197181"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4863","DOI":"10.1038\/s41467-021-25060-1","article-title":"The Extracellular Chaperone Clusterin Enhances Tau Aggregate Seeding in a Cellular Model","volume":"12","author":"Trinkaus","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"35732","DOI":"10.1074\/jbc.M113.529271","article-title":"Clusterin Is a Ligand for Apolipoprotein e Receptor 2 (ApoER2) and Very Low Density Lipoprotein Receptor (VLDLR) and Signals via the Reelin-Signaling Pathway","volume":"289","author":"Leeb","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Cho, E., Park, J., Kim, K., Kim, M., and Cho, S.R. (2021). Reelin Alleviates Mesenchymal Stem Cell Senescence and Reduces Pathological \u03b1-Synuclein Expression in an in Vitro Model of Parkinson\u2019s Disease. Genes, 12.","DOI":"10.3390\/genes12071066"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6958","DOI":"10.1074\/jbc.M115.689539","article-title":"Clusterin Binds to A\u03b21-42 Oligomers with High Affinity and Interferes with Peptide Aggregation by Inhibiting Primary and Secondary Nucleation","volume":"291","author":"Beeg","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13024-020-00416-1","article-title":"Astrocyte-Derived Clusterin Suppresses Amyloid Formation in Vivo","volume":"15","author":"Wojtas","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s40478-020-01079-1","article-title":"Clusterin Ameliorates Tau Pathology in Vivo by Inhibiting Fibril Formation","volume":"8","author":"Wojtas","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.nbd.2017.03.007","article-title":"Internalization, Axonal Transport and Release of Fibrillar Forms of Alpha-Synuclein","volume":"109","author":"Bieri","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"435","DOI":"10.3390\/biom5020435","article-title":"The Interplay between Alpha-Synuclein Clearance and Spreading","volume":"5","author":"Outeiro","year":"2015","journal-title":"Biomolecules"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Deyell, J.S., Sriparna, M., Ying, M., and Mao, X. (2023). The Interplay between \u03b1-Synuclein and Microglia in \u03b1-Synucleinopathies. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032477"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.mcn.2017.04.009","article-title":"Extensive Uptake of \u03b1-Synuclein Oligomers in Astrocytes Results in Sustained Intracellular Deposits and Mitochondrial Damage","volume":"82","author":"Gustafsson","year":"2017","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s00401-017-1746-2","article-title":"\u03b1-Synuclein Transfer between Neurons and Astrocytes Indicates That Astrocytes Play a Role in Degradation Rather than in Spreading","volume":"134","author":"Loria","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1111\/jnc.13743","article-title":"Proteolysis of \u03b1-Synuclein Fibrils in the Lysosomal Pathway Limits Induction of Inclusion Pathology","volume":"140","author":"Sacino","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.tins.2017.04.001","article-title":"The Role of Astrocyte Dysfunction in Parkinson\u2019s Disease Pathogenesis","volume":"40","author":"Booth","year":"2017","journal-title":"Trends Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1016\/j.neuron.2023.05.006","article-title":"An Astrocyte BMAL1-BAG3 Axis Protects against Alpha-Synuclein and Tau Pathology","volume":"111","author":"Sheehan","year":"2023","journal-title":"Neuron"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/glia.22619","article-title":"Apolipoproteins E and J Interfere with Amyloid-Beta Uptake by Primary Human Astrocytes and Microglia in Vitro","volume":"62","author":"Mulder","year":"2014","journal-title":"Glia"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1002\/glia.21004","article-title":"Astrocytic A\u03b21-42 Uptake Is Determined by A\u03b2-Aggregation State and the Presence of Amyloid-Associated Proteins","volume":"58","author":"Nielsen","year":"2010","journal-title":"Glia"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13024-023-00611-w","article-title":"BACE1 Regulates Expression of Clusterin in Astrocytes for Enhancing Clearance of \u03b2-Amyloid Peptides","volume":"18","author":"Zhou","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1097\/00001756-199908020-00009","article-title":"Dementia, Gliosis and Expression of the Small Heat Shock Proteins Hsp27 and AB-Crystallin in Parkinson\u2019s Disease","volume":"10","author":"Renkawek","year":"1999","journal-title":"Neuroreport"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1365-2990.2006.00689.x","article-title":"Specific Association of Small Heat Shock Proteins with the Pathological Hallmarks of Alzheimer\u2019s Disease Brains","volume":"32","author":"Wilhelmus","year":"2006","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"887","DOI":"10.7150\/ijms.107159","article-title":"Clusterin: Structure, Function and Roles in Disease","volume":"22","author":"Du","year":"2025","journal-title":"Int. J. Med. Sci."},{"key":"ref_82","first-page":"1358","article-title":"CSF Markers of Neurodegeneration in Parkinson\u2019s Disease","volume":"117","author":"Stejskal","year":"2010","journal-title":"J. Neural Transm."},{"key":"ref_83","first-page":"178","article-title":"Tau Protein, Beta-Amyloid1-42 and Clusterin CSF Levels in the Differential Diagnosis of Parkinsonian Syndrome with Dementia","volume":"343","author":"Strnad","year":"2014","journal-title":"J. Neurol. Sci."},{"key":"ref_84","first-page":"294","article-title":"Clusterin CSF Levels in Differential Diagnosis of Neurodegenerative Disorders","volume":"361","author":"Vranova","year":"2016","journal-title":"J. Neurol. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1179\/1743132812Y.0000000063","article-title":"Cerebrospinal Fluid Biomarkers of Neuropathologically Diagnosed Parkinson\u2019s Disease Subjects","volume":"34","author":"Maarouf","year":"2012","journal-title":"Neurol. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"15226","DOI":"10.1073\/pnas.1821409116","article-title":"\u03b1-Synuclein\u2212lipoprotein Interactions and Elevated ApoE Level in Cerebrospinal Fluid from Parkinson\u2019s Disease Patients","volume":"116","author":"Paslawski","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"105765","DOI":"10.1016\/j.parkreldis.2023.105765","article-title":"Elevated ApoE, ApoJ and Lipoprotein-Bound \u03b1-Synuclein Levels in Cerebrospinal Fluid from Parkinson\u2019s Disease Patients\u2014Validation in the BioFIND Cohort","volume":"116","author":"Paslawski","year":"2023","journal-title":"Park. Relat. Disord."},{"key":"ref_88","first-page":"377","article-title":"Normal Levels of Clusterin in Cerebrospinal Fluid in Alzheimer\u2019s Disease, and No Change after Acute Ischemic Stroke","volume":"3","author":"Hesse","year":"2001","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_89","first-page":"839","article-title":"Cerebrospinal Fluid and Plasma Clusterin Levels in Parkinson\u2019s Disease","volume":"19","author":"Jongbloed","year":"2013","journal-title":"Park. Relat. Disord."},{"key":"ref_90","first-page":"690","article-title":"Cerebrospinal Fluid and Blood Serum Biomarkers in Neurodegenerative Proteinopathies: A Prospective, Open, Cross-Correlation Study","volume":"167","author":"Otruba","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_91","first-page":"4628","article-title":"Quantitative Proteomic Analysis of Serum Proteins in Patients with Parkinson\u2019s Disease Using an Isobaric Tag for Relative and Absolute Quantification Labeling, Two-Dimensional Liquid Chromatography, and Tandem Mass Spectrometry","volume":"137","author":"Zhang","year":"2012","journal-title":"Analyst"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1007\/s12035-022-03139-0","article-title":"Endoplasmic Reticulum Stress-Regulated Chaperones as a Serum Biomarker Panel for Parkinson\u2019s Disease","volume":"60","author":"Mnich","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e17478","DOI":"10.1097\/MD.0000000000017478","article-title":"Differential Proteomic Analysis of Serum Exosomes Reveals Alterations in Progression of Parkinson Disease","volume":"98","author":"Jiang","year":"2019","journal-title":"Medicine"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1002\/mds.28591","article-title":"Validation of \u03b1-Synuclein in L1CAM-Immunocaptured Exosomes as a Biomarker for the Stratification of Parkinsonian Syndromes","volume":"36","author":"Jiang","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1136\/jnnp-2019-322588","article-title":"Serum Neuronal Exosomes Predict and Differentiate Parkinson\u2019s Disease from Atypical Parkinsonism","volume":"91","author":"Jiang","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15761\/JCMM.1000102","article-title":"Plasma Levels of Clusterin Are Representative of the Early Phase of the Neurodegenerative Process in Parkinson\u2019s Disease","volume":"1","author":"Polimeno","year":"2018","journal-title":"J. Clin. Mol. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e3302","DOI":"10.1002\/jgm.3302","article-title":"Association of CLU Gene Polymorphism with Parkinson\u2019s Disease in the Chinese Han Population","volume":"23","author":"Lin","year":"2021","journal-title":"J. Gene Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.neuroscience.2018.09.017","article-title":"Proteomic Profiling of Exosomal Proteins for Blood-Based Biomarkers in Parkinson\u2019s Disease","volume":"392","author":"Kitamura","year":"2018","journal-title":"Neuroscience"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3492","DOI":"10.1016\/j.celrep.2018.05.074","article-title":"Single-Molecule Characterization of the Interactions between Extracellular Chaperones and Toxic \u03b1-Synuclein Oligomers","volume":"23","author":"Whiten","year":"2018","journal-title":"Cell Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1093\/brain\/awm318","article-title":"The Role of Autophagy-Lysosome Pathway in Neurodegeneration Associated with Parkinson\u2019s Disease","volume":"131","author":"Pan","year":"2008","journal-title":"Brain"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Joshi, N., Raveendran, A., and Nagotu, S. (2020). Chaperones and Proteostasis: Role in Parkinson\u2019s Disease. Diseases, 8.","DOI":"10.3390\/diseases8020024"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Silvestro, S., Raffaele, I., and Mazzon, E. (2023). Modulating Stress Proteins in Response to Therapeutic Interventions for Parkinson\u2019sDisease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216233"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.neuroscience.2024.01.010","article-title":"Secretory Clusterin Inhibits Dopamine Neuron Apoptosis in MPTP Mice by Preserving Autophagy Activity","volume":"540","author":"Zhu","year":"2024","journal-title":"Neuroscience"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6351\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:02:31Z","timestamp":1760032951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6351"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,1]]},"references-count":103,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136351"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136351","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,1]]}}}