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Cited by 68Parkinson's Disease Mechanisms and TreatmentsAdvanced Proteomics Techniques and ApplicationsLysosomal Storage Disorders Research

A proteogenomic view of Parkinson’s disease causality and heterogeneity

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Kaiser, Sergio, Zhang, Luqing, Mollenhauer, Brit, Jacob, Jaison, Longerich, Simonne, Del-Aguila, Jorge, Marcus, Jacob, Raghavan, Neha +21 more·2023·npj Parkinson's Disease
DOI 10.1038/s41531-023-00461-9PMC PMC9922273

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Abstract

The pathogenesis and clinical heterogeneity of Parkinson’s disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into “endotypes”. The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.

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Authors
Kaiser, S., Zhang, L., Mollenhauer, B., Jacob, J., Longerich, S., Del-Aguila, J., Marcus, J., Raghavan, N., Stone, D., Fagboyegun, O., Galasko, D., Dakna, M., Bilican, B., Dovlatyan, M., Kostikova, A., Li, J., Peterson, B., Rotte, M., Sanz, V., Foroud, T., Hutten, S. J., Frasier, M., Iwaki, H., Singleton, A., Marek, K., Crawford, K., Elwood, F., Messa, M., & Serrano-Fernandez, P.
Affiliations
  • Novartis Institutes for BioMedical Research (CH)
  • Universitätsmedizin Göttingen (DE)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • Cerevel Therapeutics (United States) (US)
  • University of Southern California (US)
  • AstraZeneca (Sweden) (SE)
  • Indiana University Indianapolis (US)
  • Michael J. Fox Foundation (US)
  • National Institutes of Health (US)
Corresponding author
Messa, Mirko
ORCID
Venue
npj Parkinson's Disease
Publisher
Springer Science and Business Media LLC
Published
2023-02-11
Volume
9
Issue
1
Pages
24-24
ISSN
2373-8057 (ISSN-L)
DOI
10.1038/s41531-023-00461-9
PMC
PMC9922273
OpenAlex
W4320040276
Cited by
68
References
4
Citations by year
2026: 23 · 2025: 13 · 2024: 24 · 2023: 7 · 2022: 1
FWCI
10.93
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Parkinson s Disease (publishedVersion, cc-by)
  • medRxiv (acceptedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • The Novartis Repository (Novartis) (submittedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • School of Medicine, Indiana University
  • Novartis Institutes for BioMedical Research
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
Parkinson's disease, cerebrospinal fluid proteomics, proteogenomics, protein quantitative trait loci, Mendelian randomization, causal proteins, GPNMB, LRRK2 mutation carriers, idiopathic Parkinson's disease, disease endotypes, neuroinflammation, dopaminergic neuron loss, lysosomal degradation, mitochondrial dysfunction, oxidative stress, iron metabolism, dopamine metabolism, personalized medicine, neurodegeneration

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