The role of dopaminergic medication and specific pathway alterations in idiopathic and PRKN/PINK1-mediated Parkinson’s disease

Alexander Balck; Max Borsche; Philip Campbell; Xi Luo; John Harvey; Theresa Brückmann; Charlotte Ludwig; Amy Harms; Katja Lohmann; Emmeline Brown; Huw R. Morris; Anthony H. Schapira; Thomas Hankemeier; Ronan Fleming; Silke Szymczak; Christine Klein

doi:10.1126/sciadv.adp7063

The role of dopaminergic medication and specific pathway alterations in idiopathic and PRKN/PINK1-mediated Parkinson’s disease

Alexander Balck, Max Borsche, Philip Campbell, Xi Luo, John Harvey, Theresa Brückmann, Charlotte Ludwig, Amy Harms, Katja Lohmann, Emmeline Brown, Huw R. Morris, Anthony H. Schapira, Thomas Hankemeier, Ronan Fleming, Silke Szymczak^*, Christine Klein^*

^*Korrespondierende/r Autor/-in für diese Arbeit

2 Zitate (Scopus)

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease, with a rapidly increasing prevalence worldwide. Biomarkers monitoring state and progression are urgently needed, and metabolomics from easily accessible biofluids holds the potential to elucidate pathophysiological underpinnings in PD. Several studies suggested metabolomic differences between patients and controls, but findings are controversial, and independent replication is scarce. We thus applied state-of-the-art, large-scale metabolomics in patients with idiopathic and monogenic PD and controls from two independent samples, analyzed by a strict meta-analysis approach. Thereby, we (i) debunked that l-Dopa medication and not disease status causes the most substantial metabolomic differences and (ii) identified polyamine metabolism alterations, partly, but not entirely associated with l-Dopa treatment. Furthermore, we found explorative but robust evidence for alterations in endocannabinoid metabolites; detected lipid metabolism alterations, highlighting potential crosslinks with alpha-synuclein pathology; and provided evidence for a metabolomic signature for the role of oxidative damage in patients with PRKN- and PINK1-linked PD.

Originalsprache	Englisch
Aufsatznummer	eadp7063
Zeitschrift	Science Advances
Jahrgang	11
Ausgabenummer	20
DOIs	https://doi.org/10.1126/sciadv.adp7063
Publikationsstatus	Veröffentlicht - 16.05.2025

Fördermittel

We thank the study participants at both clinical recruitment sites for their willingness to support our research. The project was funded by the EU Horizon 2020 programme, grant agreement 668738 (SysMedPD). The German Research Foundation (DFG) funded A.B.’s research stay at Leiden, the Netherlands. X.L. is funded by a Chinese Scholarship Council (CSC) scholarship (grant number 202006370070). Acknowledgments: We thank the study participants at both clinical recruitment sites for their willingness to support our research. Funding: the project was funded by the eU horizon 2020 programme, grant agreement 668738 (SysMedPd). the German Research Foundation (dFG) funded A.B.’s research stay at leiden, the netherlands. X.l. is funded by a chinese Scholarship council (cSc) scholarship (grant number 202006370070). Author contributions: A.B.: Writing—original draft, conceptualization, investigation, methodology, resources, data curation, validation, formal analysis, project administration, and visualization. M.B.: Writing— original draft, conceptualization, investigation, methodology, resources, project administration, and visualization. P.c.: conceptualization, writing—review and editing, methodology, and resources. X.l.: Writing—review and editing and validation. J.h.: Writing— review and editing and resources. t.B.: investigation, Writing—review and editing, methodology, resources, data curation, validation, formal analysis, and project administration. c.l.: investigation, writing—review and editing, methodology, and resources. A.h.: investigation, writing—review and editing, and methodology. K.l.: Writing—review and editing, resources, and validation. e.B.: Writing – review and editing, resources, data curation, and formal analysis. h.R.M.: conceptualization, investigation, writing—review and editing, methodology, funding acquisition, supervision, and project administration. A.h.S.: conceptualization, investigation, writing—review and editing, methodology, resources, funding acquisition, validation, and project administration. t.h.: Writing—review and editing, methodology, funding acquisition, supervision. R.F.: Writing—review and editing, methodology, and supervision. S.S.: conceptualization, writing—review and editing, data curation, formal analysis, and visualization. c.K.: conceptualization, investigation, writing— review and editing, methodology, resources, funding acquisition, data curation, validation, supervision, and project administration. Competing interests: the authors declare that they have no competing interests. Data and materials availability: the raw data supporting this study’s findings were uploaded to Zenodo (https://zenodo.org/records/15124574). in addition,

Träger	Trägernummer
Deutsche Forschungsgemeinschaft
Horizon 2020 Framework Programme	668738
China Scholarship Council	202006370070

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Querschnittsbereich: Medizinische Genetik

DFG-Fachsystematik

2.23-06 Molekulare und zelluläre Neurologie und Neuropathologie

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10.1126/sciadv.adp7063

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Balck, A., Borsche, M., Campbell, P., Luo, X., Harvey, J., Brückmann, T., Ludwig, C., Harms, A., Lohmann, K., Brown, E., Morris, H. R., Schapira, A. H., Hankemeier, T., Fleming, R., Szymczak, S., & Klein, C. (2025). The role of dopaminergic medication and specific pathway alterations in idiopathic and PRKN/PINK1-mediated Parkinson’s disease. Science Advances, 11(20), Artikel eadp7063. https://doi.org/10.1126/sciadv.adp7063

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title = "The role of dopaminergic medication and specific pathway alterations in idiopathic and PRKN/PINK1-mediated Parkinson{\textquoteright}s disease",

abstract = "Parkinson{\textquoteright}s disease (PD) is the second most common neurodegenerative disease, with a rapidly increasing prevalence worldwide. Biomarkers monitoring state and progression are urgently needed, and metabolomics from easily accessible biofluids holds the potential to elucidate pathophysiological underpinnings in PD. Several studies suggested metabolomic differences between patients and controls, but findings are controversial, and independent replication is scarce. We thus applied state-of-the-art, large-scale metabolomics in patients with idiopathic and monogenic PD and controls from two independent samples, analyzed by a strict meta-analysis approach. Thereby, we (i) debunked that l-Dopa medication and not disease status causes the most substantial metabolomic differences and (ii) identified polyamine metabolism alterations, partly, but not entirely associated with l-Dopa treatment. Furthermore, we found explorative but robust evidence for alterations in endocannabinoid metabolites; detected lipid metabolism alterations, highlighting potential crosslinks with alpha-synuclein pathology; and provided evidence for a metabolomic signature for the role of oxidative damage in patients with PRKN- and PINK1-linked PD.",

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Balck, A , Borsche, M, Campbell, P, Luo, X, Harvey, J, Brückmann, T, Ludwig, C, Harms, A, Lohmann, K, Brown, E, Morris, HR, Schapira, AH, Hankemeier, T, Fleming, R, Szymczak, S & Klein, C 2025, 'The role of dopaminergic medication and specific pathway alterations in idiopathic and PRKN/PINK1-mediated Parkinson’s disease', Science Advances, Jg. 11, Nr. 20, eadp7063. https://doi.org/10.1126/sciadv.adp7063

TY - JOUR

T1 - The role of dopaminergic medication and specific pathway alterations in idiopathic and PRKN/PINK1-mediated Parkinson’s disease

AU - Balck, Alexander

AU - Borsche, Max

AU - Campbell, Philip

AU - Luo, Xi

AU - Harvey, John

AU - Brückmann, Theresa

AU - Ludwig, Charlotte

AU - Harms, Amy

AU - Lohmann, Katja

AU - Brown, Emmeline

AU - Morris, Huw R.

AU - Schapira, Anthony H.

AU - Hankemeier, Thomas

AU - Fleming, Ronan

AU - Szymczak, Silke

AU - Klein, Christine

PY - 2025/5/16

Y1 - 2025/5/16

N2 - Parkinson’s disease (PD) is the second most common neurodegenerative disease, with a rapidly increasing prevalence worldwide. Biomarkers monitoring state and progression are urgently needed, and metabolomics from easily accessible biofluids holds the potential to elucidate pathophysiological underpinnings in PD. Several studies suggested metabolomic differences between patients and controls, but findings are controversial, and independent replication is scarce. We thus applied state-of-the-art, large-scale metabolomics in patients with idiopathic and monogenic PD and controls from two independent samples, analyzed by a strict meta-analysis approach. Thereby, we (i) debunked that l-Dopa medication and not disease status causes the most substantial metabolomic differences and (ii) identified polyamine metabolism alterations, partly, but not entirely associated with l-Dopa treatment. Furthermore, we found explorative but robust evidence for alterations in endocannabinoid metabolites; detected lipid metabolism alterations, highlighting potential crosslinks with alpha-synuclein pathology; and provided evidence for a metabolomic signature for the role of oxidative damage in patients with PRKN- and PINK1-linked PD.

AB - Parkinson’s disease (PD) is the second most common neurodegenerative disease, with a rapidly increasing prevalence worldwide. Biomarkers monitoring state and progression are urgently needed, and metabolomics from easily accessible biofluids holds the potential to elucidate pathophysiological underpinnings in PD. Several studies suggested metabolomic differences between patients and controls, but findings are controversial, and independent replication is scarce. We thus applied state-of-the-art, large-scale metabolomics in patients with idiopathic and monogenic PD and controls from two independent samples, analyzed by a strict meta-analysis approach. Thereby, we (i) debunked that l-Dopa medication and not disease status causes the most substantial metabolomic differences and (ii) identified polyamine metabolism alterations, partly, but not entirely associated with l-Dopa treatment. Furthermore, we found explorative but robust evidence for alterations in endocannabinoid metabolites; detected lipid metabolism alterations, highlighting potential crosslinks with alpha-synuclein pathology; and provided evidence for a metabolomic signature for the role of oxidative damage in patients with PRKN- and PINK1-linked PD.

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M3 - Journal articles

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AN - SCOPUS:105005473517

SN - 2375-2548

VL - 11

JO - Science Advances

JF - Science Advances

IS - 20

M1 - eadp7063

ER -

The role of dopaminergic medication and specific pathway alterations in idiopathic and PRKN/PINK1-mediated Parkinson’s disease

Abstract

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