Cystatin C Secretion in Blood Derivatives and Cellular Models of Idiopathic Parkinson's Disease.

[en] Parkinson's disease is an age-related progressive neurodegenerative disorder. A large majority of Parkinson's disease patients have an unknown etiology, which is classified as idiopathic Parkinson's disease. Generating disease models directly from idiopathic Parkinson's disease patients may improve the understanding of the disease pathology. Both neuroprotective and neurodegenerative roles have been suggested for cystatin C in neurodegenerative disease. In Parkinson's disease, investigations assessing cystatin C levels in different types of biospecimens such as blood, cerebrospinal fluid, and in vitro models have had conflicting results. We present a study assessing cystatin C levels in different biospecimen types originating from the same subjects. Using a sandwich ELISA, we compared cystatin C concentration in blood derivatives (plasma and serum) and culture media of derived models (stem cells, neuroepithelial stem cells, and midbrain organoids) of three idiopathic Parkinson's disease and three age-matched healthy control subjects with the same CST3 genotype. Genotyping analyses confirmed that all subjects were homozygous AA. The identity of the derived models was confirmed using immunohistochemical staining. Secreted cystatin C concentration was measured in each biospecimen tested. No statistically significant differences in cystatin C concentrations were found between the subjects in any of the biospecimen types. As a personalized marker, a higher cystatin C concentration was shown for some individual patients in the culture medium of midbrain organoids, suggesting a potential involvement in Parkinson's disease physiopathology. This proof of concept demonstrates that cystatin C is secreted by various idiopathic Parkinson's disease cell models, including midbrain organoids, which in turn suggests that cystatin C secretion by midbrain organoids might be pertinent in neurodegenerative disease research.

Disciplines :

Life sciences: Multidisciplinary, general & others

Author, co-author :

Mommaerts, Kathleen ; Integrated Biobank of Luxembourg, Luxembourg Institute of Health, Dudelange, Luxembourg ; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg

Monzel, Anna S ; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg

ZAGARE, Alise ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN

NICKELS, Sarah ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN

DIEDERICH, Nico ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Scientific Central Services > Disease Modelling and Screening Platform ; Department of Neurosciences, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg

LONGHINO, Laura ; University of Luxembourg ; Department of Neurosciences, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg

Mathieson, William ; Integrated Biobank of Luxembourg, Luxembourg Institute of Health, Dudelange, Luxembourg

ANTONY, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Imaging Platform

BETSOU, Fay ; University of Luxembourg ; Centre de Ressources Biologiques de l'Institut Pasteur, Institut Pasteur, Paris, France

SCHWAMBORN, Jens Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology

External co-authors :

yes

Language :

English

Title :

Cystatin C Secretion in Blood Derivatives and Cellular Models of Idiopathic Parkinson's Disease.

Publication date :

24 January 2025

Journal title :

Parkinson's Disease

ISSN :

2090-8083

eISSN :

2042-0080

Publisher :

John Wiley and Sons Ltd, United States

Volume :

2025

Issue :

Pages :

5149071

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://onlinelibrary.wiley.com/doi/pdf/10.1155/padi/5149071

FnR Project :

FNR/NCER13/BM/11264123

Funding text :

This work was supported by the National Center of Excellence in Research on Parkinson\u2019s Disease, using funds from the Luxembourg National Research Fund (FNR/NCER13/BM/11264123). The technical assistance on the Mann\u2013Whitney U test of Gwena\u00EBlle Le Coroller is gratefully acknowledged. We thank Estelle Sandt and Angela Hogan for providing clinical data, Inga Werthschulte for reprogramming training, and Jonas Walter for iPSCs characterization.This work was supported by the National Center of Excellence in Research on Parkinson\u2019s Disease, using funds from the Luxembourg National Research Fund (FNR/NCER13/BM/11264123).

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since 20 January 2026

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Bibliography

Selvaraj S. and Piramanayagam S., Impact of Gene Mutation in the Development of Parkinson’s Disease, Genes & Diseases. (2019) 6, no. 2, 120–128, https://doi.org/10.1016/j.gendis.2019.01.004, 2-s2.0-85064256197.
Gauthier S., Kaur G., Mi W., Tizon B., and Levy E., Protective Mechanisms by Cystatin C in Neurodegenerative Diseases, Frontiers in Bioscience. (2011) 3, no. 2, 541–554, https://doi.org/10.2741/s170.
Nagai A., Ryu J. K., Kobayash S., and Kim S. U., Cystatin C Induces Neuronal Cell Death In Vivo, Annals of the New York Academy of Sciences. (2002) 977, no. 1, 315–321, https://doi.org/10.1111/j.1749-6632.2002.tb04832.x, 2-s2.0-0036450040.
Martinez-Vargas M., Soto-Nuñez M., Tabla-Ramon E. et al., Cystatin C Has a Dual Role in Post-Traumatic Brain Injury Recovery, International Journal of Molecular Sciences. (2014) 15, no. 4, 5807–5820, https://doi.org/10.3390/ijms15045807, 2-s2.0-84898738246.
Suzuki Y., Jin C., and Yazawa I., Cystatin C Triggers Neuronal Degeneration in a Model of Multiple System Atrophy, The American Journal of Pathology. (2014) 184, no. 3, 790–799, https://doi.org/10.1016/j.ajpath.2013.11.018, 2-s2.0-84894197966.
Li J., Gu C., Zhu M., Li D., Chen L., and Zhu X., Correlations Between Blood Lipid, Serum Cystatin C, and Homocysteine Levels in Patients With Parkinson’s Disease, Psychogeriatrics. (2020) 20, no. 2, 180–188, https://doi.org/10.1111/psyg.12483.
Xiong K. P., Dai Y. P., Chen J. et al., Increased Serum Cystatin C in Early Parkinson’s Disease With Objective Sleep Disturbances, Chinese Medical Journal. (2018) 131, no. 8, 907–911, https://doi.org/10.4103/0366-6999.229902, 2-s2.0-85045532831.
Abrahamson M., Olafsson I., Palsdottir A. et al., Structure and Expression of the Human Cystatin C Gene, Biochemical Journal. (1990) 268, no. 2, 287–294, https://doi.org/10.1042/bj2680287, 2-s2.0-0025303610.
Löfberg H. and Grubb A. O., Quantitation of Gamma-Trace in Human Biological Fluids: Indications for Production in the Central Nervous System, Scandinavian Journal of Clinical and Laboratory Investigation. (1979) 39, no. 7, 619–626, https://doi.org/10.3109/00365517909108866, 2-s2.0-0018718823.
Finckh U., von der Kammer H., Velden J. et al., Genetic Association of a Cystatin C Gene Polymorphism With Late-Onset Alzheimer Disease, Archives of Neurology. (2000) 57, no. 11, 1579–1583, https://doi.org/10.1001/archneur.57.11.1579, 2-s2.0-0033733370.
Ólafsson Í., The Human Cystatin C Gene Promoter: Functional Analysis and Identification of Heterogeneous mRNA, Scandinavian Journal of Clinical and Laboratory Investigation. (1995) 55, no. 7, 597–607, https://doi.org/10.3109/00365519509110259, 2-s2.0-0028839207.
Benussi L., Ghidoni R., Steinhoff T. et al., Alzheimer Disease-Associated Cystatin C Variant Undergoes Impaired Secretion, Neurobiology of Disease. (2003) 13, no. 1, 15–21, https://doi.org/10.1016/s0969-9961(03)00012-3, 2-s2.0-0038399757.
Newman D. J., Cystatin C, Annals of Clinical Biochemistry: International Journal of Laboratory Medicine. (2002) 39, no. 2, 89–104, https://doi.org/10.1258/0004563021901847, 2-s2.0-0036188611.
Collier T. J., Kanaan N. M., and Kordower J. H., Ageing as a Primary Risk Factor for Parkinson’s Disease: Evidence From Studies of Non-Human Primates, Nature Reviews Neuroscience. (2011) 12, no. 6, 359–366, https://doi.org/10.1038/nrn3039, 2-s2.0-79957467314.
Pottel H., Björk J., Rule A. D. et al., Cystatin C-Based Equation to Estimate GFR Without the Inclusion of Race and Sex, New England Journal of Medicine. (2023) 388, no. 4, 333–343, https://doi.org/10.1056/NEJMoa2203769.
Mommaerts K., Bellora C., Lambert P., Türkmen S., Schwamborn J. C., and Betsou F., Method Optimization of Skin Biopsy-Derived Fibroblast Culture for Reprogramming into Induced Pluripotent Stem Cells, Biopreservation and Biobanking. (2022) 20, no. 1, 12–23, https://doi.org/10.1089/bio.2020.0159.
MacCarthy C. M., Malik V., Wu G. et al., Enhancing Sox/Oct Cooperativity Induces Higher-Grade Developmental Reset, bioRxiv. (2022) 2022, https://doi.org/10.1101/2022.09.23.509242.
Reinhardt P., Glatza M., Hemmer K. et al., Derivation and Expansion Using Only Small Molecules of Human Neural Progenitors for Neurodegenerative Disease Modeling, PLoS One. (2013) 8, no. 3, https://doi.org/10.1371/journal.pone.0059252, 2-s2.0-84875284468.
Monzel A. S., Smits L. M., Hemmer K. et al., Derivation of Human Midbrain-Specific Organoids From Neuroepithelial Stem Cells, Stem Cell Reports. (2017) 8, no. 5, 1144–1154, https://doi.org/10.1016/j.stemcr.2017.03.010, 2-s2.0-85017459346.
Zagare A., Contribution of Type 2 Diabetes and Genetic Variants in LRRK2 and GBA to Parkinson’s Disease, 2023, Unilu-University of Luxembourg.
Zagare A., Gobin M., Monzel A. S., and Schwamborn J. C., A Robust Protocol for the Generation of Human Midbrain Organoids, STAR Protocols. (2021) 2, no. 2, https://doi.org/10.1016/j.xpro.2021.100524.
Mommaerts K., Willemse E. A. J., Marchese M. et al., A Cystatin C Cleavage ELISA Assay as a Quality Control Tool for Determining Sub-Optimal Storage Conditions of Cerebrospinal Fluid Samples in Alzheimer’s Disease Research, Journal of Alzheimer’s Disease. (2021) 83, no. 3, 1367–1377, https://doi.org/10.3233/jad-210741.
Maniwa K., Yano S., Sheikh A. M. et al., Association Between Cystatin C Gene Polymorphism and the Prevalence of White Matter Lesion in Elderly Healthy Subjects, Scientific Reports. (2020) 10, no. 1, https://doi.org/10.1038/s41598-020-61383-7.
Spithoven E. M., Bakker S. J., Kootstra-Ros J. E., de Jong P. E., and Gansevoort R. T., Stability of Creatinine and Cystatin C in Whole Blood, Clinical Biochemistry. (2013) 46, no. 15, 1611–1614, https://doi.org/10.1016/j.clinbiochem.2013.06.022, 2-s2.0-84884354799.
Yang C. G., Cai S. M., Liu C. Y., and Chen C., On the Correlation Between Serum Cystatin C and Parkinson’s Disease in the Chinese Population: A Promising Biomarker?, Journal of Integrative Neuroscience. (2021) 20, no. 2, 349–357, https://doi.org/10.31083/j.jin2002034.
Hu W. D., Chen J., Mao C. J. et al., Elevated Cystatin C Levels Are Associated With Cognitive Impairment and Progression of Parkinson Disease, Cognitive and Behavioral Neurology. (2016) 29, no. 3, 144–149, https://doi.org/10.1097/wnn.0000000000000100, 2-s2.0-84989959561.
Chen W. W., Cheng X., Zhang X. et al., The Expression Features of Serum Cystatin C and Homocysteine of Parkinson’s Disease With Mild Cognitive Dysfunction, European Review for Medical and Pharmacological Sciences. (2015) 19, no. 16, 2957–2963.
Imarisio A., Pilotto A., Garrafa E. et al., Plasma Cystatin C Correlates With Plasma NfL Levels and Predicts Disease Progression in Parkinson’s Disease, Neurodegenerative Diseases. (2022) 21, no. 5-6, 109–116, https://doi.org/10.1159/000523982.
Smits L. M. and Schwamborn J. C., Midbrain Organoids: A New Tool to Investigate Parkinson’s Disease, Frontiers in Cell and Developmental Biology. (2020) 8, https://doi.org/10.3389/fcell.2020.00359.
Smits L. M., Reinhardt L., Reinhardt P. et al., Modeling Parkinson’s Disease in Midbrain-Like Organoids, NPJ Parkinson’s disease. (2019) 5, no. 1, https://doi.org/10.1038/s41531-019-0078-4.
Kim H., Park H. J., Choi H. et al., Modeling G2019S-LRRK2 Sporadic Parkinson’s Disease in 3D Midbrain Organoids, Stem Cell Reports. (2019) 12, no. 3, 518–531, https://doi.org/10.1016/j.stemcr.2019.01.020, 2-s2.0-85062101346.
Kaur G. and Levy E., Cystatin C in Alzheimer’s Disease, Frontiers in Molecular Neuroscience. (2012) 5, https://doi.org/10.3389/fnmol.2012.00079, 2-s2.0-84864015486.
Watanabe S., Hayakawa T., Wakasugi K., and Yamanaka K., Cystatin C Protects Neuronal Cells Against Mutant Copper-Zinc Superoxide Dismutase-Mediated Toxicity, Cell Death & Disease. (2014) 5, no. 10, https://doi.org/10.1038/cddis.2014.459, 2-s2.0-84928044063.
Watanabe S., Komine O., Endo F., Wakasugi K., and Yamanaka K., Intracerebroventricular Administration of Cystatin C Ameliorates Disease in SOD1-Linked Amyotrophic Lateral Sclerosis Mice, Journal of Neurochemistry. (2018) 145, no. 1, 80–89, https://doi.org/10.1111/jnc.14285, 2-s2.0-85041662105.
Kaur G., Mohan P., Pawlik M. et al., Cystatin C Rescues Degenerating Neurons in a Cystatin B-Knockout Mouse Model of Progressive Myoclonus Epilepsy, The American Journal of Pathology. (2010) 177, no. 5, 2256–2267, https://doi.org/10.2353/ajpath.2010.100461, 2-s2.0-78149329846.
Xu L., Sheng J., Tang Z. et al., Cystatin C Prevents Degeneration of Rat Nigral Dopaminergic Neurons: In Vitro and In Vivo Studies, Neurobiology of Disease. (2005) 18, no. 1, 152–165, https://doi.org/10.1016/j.nbd.2004.08.012, 2-s2.0-19944426120.
Tizon B., Ribe E. M., Mi W., Troy C. M., and Levy E., Cystatin C Protects Neuronal Cells From Amyloid-β-Induced Toxicity, Journal of Alzheimer’s Disease. (2010) 19, no. 3, 885–894, https://doi.org/10.3233/jad-2010-1291, 2-s2.0-77149131537.
Tizon B., Sahoo S., Yu H. et al., Induction of Autophagy by Cystatin C: A Mechanism that Protects Murine Primary Cortical Neurons and Neuronal Cell Lines, PLoS One. (2010) 5, no. 3, https://doi.org/10.1371/journal.pone.0009819, 2-s2.0-77956475769.
Zou J., Chen Z., Wei X. et al., Cystatin C as a Potential Therapeutic Mediator Against Parkinson’s Disease via VEGF-Induced Angiogenesis and Enhanced Neuronal Autophagy in Neurovascular Units, Cell Death & Disease. (2017) 8, no. 6, https://doi.org/10.1038/cddis.2017.240, 2-s2.0-85042409176.
Ascherio A. and Schwarzschild M. A., The Epidemiology of Parkinson’s Disease: Risk Factors and Prevention, The Lancet Neurology. (2016) 15, no. 12, 1257–1272, https://doi.org/10.1016/s1474-4422(16)30230-7, 2-s2.0-84992198065.
Gillies G. E., Pienaar I. S., Vohra S., and Qamhawi Z., Sex Differences in Parkinson’s Disease, Frontiers in Neuroendocrinology. (2014) 35, no. 3, 370–384, https://doi.org/10.1016/j.yfrne.2014.02.002, 2-s2.0-84903757648.