Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175
Abstract Parkinson’s disease (PD) represents one of the most frequent neurodegenerative disorders for which clinically useful biomarkers remain to be identified and validated. Here, we adopted an untargeted omics approach to disclose lipidomic, metabolomic and proteomic alterations in plasma and in...
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Nature Portfolio
2025-01-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-024-00853-5 |
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| author | Federica Carrillo Marco Ghirimoldi Giorgio Fortunato Nicole Piera Palomba Laura Ianiro Veronica De Giorgis Shahzaib Khoso Tiziana Giloni Sara Pietracupa Nicola Modugno Elettra Barberis Marcello Manfredi Teresa Esposito |
| author_facet | Federica Carrillo Marco Ghirimoldi Giorgio Fortunato Nicole Piera Palomba Laura Ianiro Veronica De Giorgis Shahzaib Khoso Tiziana Giloni Sara Pietracupa Nicola Modugno Elettra Barberis Marcello Manfredi Teresa Esposito |
| author_sort | Federica Carrillo |
| collection | DOAJ |
| description | Abstract Parkinson’s disease (PD) represents one of the most frequent neurodegenerative disorders for which clinically useful biomarkers remain to be identified and validated. Here, we adopted an untargeted omics approach to disclose lipidomic, metabolomic and proteomic alterations in plasma and in dermal fibroblasts of PD patients carrying mutations in TMEM175 gene. We revealed a wide dysregulation of lysosome, autophagy, and mitochondrial pathways in these patients, supporting a role of this channel in regulating these cellular processes. The most significant altered lipid classes were Fatty acyls, Glycerophospholipids and Phosphosphingolipids. The plasma level of Phosphatidylcholines (PC) and Phosphatidylinositol (PI) 34:1 significantly correlated with an earlier age at onset of the disease in TMEM175 patients (p = 0.008; p = 0.006). In plasma we also observed altered amino acids metabolic pathways in PD patients. We highlighted that increased level of L-glutamate strongly correlated (p < 0.001) with the severity of motor and non-motor symptoms in PD_TMEM175 patients. In dermal fibroblasts, we disclosed alterations of proteins involved in lipids biosynthesis (PAG15, PP4P1, GALC, FYV1, PIGO, PGPS1, PLPP1), in the insulin pathway (IGF2R), in mitochondrial metabolism (ACD10, ACD11, ACADS) and autophagy (RAB7L). Interestingly, we quantified 43 lysosomal or lysosomal-related proteins, which were differentially modulated between TMEM175 patients and controls. Integrative correlation analysis of proteome and lipidome of PD_TMEM175 cellular models identified a strong positive correlation of 13 proteins involved in biosynthetic processes with PC and Ceramides. Altogether, these data provide novel insights into the molecular and metabolic alterations underlying TMEM175 mutations and may be relevant for PD prediction, diagnosis and treatment. |
| format | Article |
| id | doaj-art-08decb3c08434986afb7a6a61c88cd7e |
| institution | Kabale University |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | npj Parkinson's Disease |
| spelling | doaj-art-08decb3c08434986afb7a6a61c88cd7e2025-01-26T12:21:30ZengNature Portfolionpj Parkinson's Disease2373-80572025-01-0111112410.1038/s41531-024-00853-5Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175Federica Carrillo0Marco Ghirimoldi1Giorgio Fortunato2Nicole Piera Palomba3Laura Ianiro4Veronica De Giorgis5Shahzaib Khoso6Tiziana Giloni7Sara Pietracupa8Nicola Modugno9Elettra Barberis10Marcello Manfredi11Teresa Esposito12Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, National Research CouncilBiological Mass Spectrometry Lab, Department of Translational Medicine, University of Piemonte OrientaleInstitute of Genetics and Biophysics “Adriano Buzzati-Traverso”, National Research CouncilIRCCS INM NeuromedIRCCS INM NeuromedBiological Mass Spectrometry Lab, Department of Translational Medicine, University of Piemonte OrientaleBiological Mass Spectrometry Lab, Department of Translational Medicine, University of Piemonte OrientaleIRCCS INM NeuromedIRCCS INM NeuromedIRCCS INM NeuromedCenter for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte OrientaleBiological Mass Spectrometry Lab, Department of Translational Medicine, University of Piemonte OrientaleInstitute of Genetics and Biophysics “Adriano Buzzati-Traverso”, National Research CouncilAbstract Parkinson’s disease (PD) represents one of the most frequent neurodegenerative disorders for which clinically useful biomarkers remain to be identified and validated. Here, we adopted an untargeted omics approach to disclose lipidomic, metabolomic and proteomic alterations in plasma and in dermal fibroblasts of PD patients carrying mutations in TMEM175 gene. We revealed a wide dysregulation of lysosome, autophagy, and mitochondrial pathways in these patients, supporting a role of this channel in regulating these cellular processes. The most significant altered lipid classes were Fatty acyls, Glycerophospholipids and Phosphosphingolipids. The plasma level of Phosphatidylcholines (PC) and Phosphatidylinositol (PI) 34:1 significantly correlated with an earlier age at onset of the disease in TMEM175 patients (p = 0.008; p = 0.006). In plasma we also observed altered amino acids metabolic pathways in PD patients. We highlighted that increased level of L-glutamate strongly correlated (p < 0.001) with the severity of motor and non-motor symptoms in PD_TMEM175 patients. In dermal fibroblasts, we disclosed alterations of proteins involved in lipids biosynthesis (PAG15, PP4P1, GALC, FYV1, PIGO, PGPS1, PLPP1), in the insulin pathway (IGF2R), in mitochondrial metabolism (ACD10, ACD11, ACADS) and autophagy (RAB7L). Interestingly, we quantified 43 lysosomal or lysosomal-related proteins, which were differentially modulated between TMEM175 patients and controls. Integrative correlation analysis of proteome and lipidome of PD_TMEM175 cellular models identified a strong positive correlation of 13 proteins involved in biosynthetic processes with PC and Ceramides. Altogether, these data provide novel insights into the molecular and metabolic alterations underlying TMEM175 mutations and may be relevant for PD prediction, diagnosis and treatment.https://doi.org/10.1038/s41531-024-00853-5 |
| spellingShingle | Federica Carrillo Marco Ghirimoldi Giorgio Fortunato Nicole Piera Palomba Laura Ianiro Veronica De Giorgis Shahzaib Khoso Tiziana Giloni Sara Pietracupa Nicola Modugno Elettra Barberis Marcello Manfredi Teresa Esposito Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175 npj Parkinson's Disease |
| title | Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175 |
| title_full | Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175 |
| title_fullStr | Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175 |
| title_full_unstemmed | Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175 |
| title_short | Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175 |
| title_sort | multiomics approach identifies dysregulated lipidomic and proteomic networks in parkinson s disease patients mutated in tmem175 |
| url | https://doi.org/10.1038/s41531-024-00853-5 |
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