A proteogenomic view of Parkinson’s disease causality and heterogeneity
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, t...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-02-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-023-00461-9 |
| _version_ | 1797422240929677312 |
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| author | Sergio Kaiser Luqing Zhang Brit Mollenhauer Jaison Jacob Simonne Longerich Jorge Del-Aguila Jacob Marcus Neha Raghavan David Stone Olumide Fagboyegun Douglas Galasko Mohammed Dakna Bilada Bilican Mary Dovlatyan Anna Kostikova Jingyao Li Brant Peterson Michael Rotte Vinicius Sanz Tatiana Foroud Samantha J. Hutten Mark Frasier Hirotaka Iwaki Andrew Singleton Ken Marek Karen Crawford Fiona Elwood Mirko Messa Pablo Serrano-Fernandez |
| author_facet | Sergio Kaiser Luqing Zhang Brit Mollenhauer Jaison Jacob Simonne Longerich Jorge Del-Aguila Jacob Marcus Neha Raghavan David Stone Olumide Fagboyegun Douglas Galasko Mohammed Dakna Bilada Bilican Mary Dovlatyan Anna Kostikova Jingyao Li Brant Peterson Michael Rotte Vinicius Sanz Tatiana Foroud Samantha J. Hutten Mark Frasier Hirotaka Iwaki Andrew Singleton Ken Marek Karen Crawford Fiona Elwood Mirko Messa Pablo Serrano-Fernandez |
| author_sort | Sergio Kaiser |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T07:29:23Z |
| format | Article |
| id | doaj.art-8a3707f40aec4528b1d8d9e56c321bac |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-09T07:29:23Z |
| publishDate | 2023-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-8a3707f40aec4528b1d8d9e56c321bac2023-12-03T06:45:44ZengNature Portfolionpj Parkinson's Disease2373-80572023-02-019111310.1038/s41531-023-00461-9A proteogenomic view of Parkinson’s disease causality and heterogeneitySergio Kaiser0Luqing Zhang1Brit Mollenhauer2Jaison Jacob3Simonne Longerich4Jorge Del-Aguila5Jacob Marcus6Neha Raghavan7David Stone8Olumide Fagboyegun9Douglas Galasko10Mohammed Dakna11Bilada Bilican12Mary Dovlatyan13Anna Kostikova14Jingyao Li15Brant Peterson16Michael Rotte17Vinicius Sanz18Tatiana Foroud19Samantha J. Hutten20Mark Frasier21Hirotaka Iwaki22Andrew Singleton23Ken Marek24Karen Crawford25Fiona Elwood26Mirko Messa27Pablo Serrano-Fernandez28Translational Medicine Department, Novartis Institutes for Biomedical ResearchCardiovascular and Metabolism Department, Novartis Institutes for Biomedical ResearchDepartment of Neurology, University Medical Center GöttingenCardiovascular and Metabolism Department, Novartis Institutes for Biomedical ResearchGenome and Biomarker Sciences, Merck Exploratory Science CenterGenome and Biomarker Sciences, Merck Exploratory Science CenterGenome and Biomarker Sciences, Merck Exploratory Science CenterGenome and Biomarker Sciences, Merck Exploratory Science CenterDepartment of Genetics, Cerevel TherapeuticsDepartment of Genetics, Cerevel TherapeuticsDepartment of Neurosciences, University of Southern California, San DiegoDepartment of Neurology, University Medical Center GöttingenNeuroscience Department, Novartis Institutes for Biomedical ResearchNeuroscience Department, Novartis Institutes for Biomedical ResearchTranslational Medicine Department, Novartis Institutes for Biomedical ResearchNeuroscience Department, Novartis Institutes for Biomedical ResearchNeuroscience Department, Novartis Institutes for Biomedical ResearchTranslational Medicine Department, Novartis Institutes for Biomedical ResearchNeuroscience Department, Novartis Institutes for Biomedical ResearchDepartment of Medical and Molecular Genetics, Indiana University School of MedicineMichael J. Fox Foundation for Parkinson’s ResearchMichael J. Fox Foundation for Parkinson’s ResearchLaboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthLaboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthInstitute for Neurodegenerative DisordersLaboratory of Neuroimaging, University of Southern CaliforniaNeuroscience Department, Novartis Institutes for Biomedical ResearchNeuroscience Department, Novartis Institutes for Biomedical ResearchTranslational Medicine Department, Novartis Institutes for Biomedical ResearchAbstract 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.https://doi.org/10.1038/s41531-023-00461-9 |
| spellingShingle | Sergio Kaiser Luqing Zhang Brit Mollenhauer Jaison Jacob Simonne Longerich Jorge Del-Aguila Jacob Marcus Neha Raghavan David Stone Olumide Fagboyegun Douglas Galasko Mohammed Dakna Bilada Bilican Mary Dovlatyan Anna Kostikova Jingyao Li Brant Peterson Michael Rotte Vinicius Sanz Tatiana Foroud Samantha J. Hutten Mark Frasier Hirotaka Iwaki Andrew Singleton Ken Marek Karen Crawford Fiona Elwood Mirko Messa Pablo Serrano-Fernandez A proteogenomic view of Parkinson’s disease causality and heterogeneity npj Parkinson's Disease |
| title | A proteogenomic view of Parkinson’s disease causality and heterogeneity |
| title_full | A proteogenomic view of Parkinson’s disease causality and heterogeneity |
| title_fullStr | A proteogenomic view of Parkinson’s disease causality and heterogeneity |
| title_full_unstemmed | A proteogenomic view of Parkinson’s disease causality and heterogeneity |
| title_short | A proteogenomic view of Parkinson’s disease causality and heterogeneity |
| title_sort | proteogenomic view of parkinson s disease causality and heterogeneity |
| url | https://doi.org/10.1038/s41531-023-00461-9 |
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