Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease
Abstract Deficits in protein synthesis are associated with Parkinson’s disease (PD). However, it is not known which proteins are affected or if there are synthesis differences between patients with sporadic and Leucine-Rich Repeat Kinase 2 (LRRK2) G2019S PD, the most common monogenic form. Here we u...
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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/s41531-023-00460-w |
| _version_ | 1797422242239348736 |
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| author | Dani Flinkman Ye Hong Jelena Gnjatovic Prasannakumar Deshpande Zsuzsanna Ortutay Sirkku Peltonen Valtteri Kaasinen Peter James Eleanor Coffey |
| author_facet | Dani Flinkman Ye Hong Jelena Gnjatovic Prasannakumar Deshpande Zsuzsanna Ortutay Sirkku Peltonen Valtteri Kaasinen Peter James Eleanor Coffey |
| author_sort | Dani Flinkman |
| collection | DOAJ |
| description | Abstract Deficits in protein synthesis are associated with Parkinson’s disease (PD). However, it is not known which proteins are affected or if there are synthesis differences between patients with sporadic and Leucine-Rich Repeat Kinase 2 (LRRK2) G2019S PD, the most common monogenic form. Here we used bio-orthogonal non-canonical amino acid tagging for global analysis of newly translated proteins in fibroblasts from sporadic and LRKK2-G2019S patients. Quantitative proteomic analysis revealed that several nascent proteins were reduced in PD samples compared to healthy without any significant change in mRNA levels. Using targeted proteomics, we validated which of these proteins remained dysregulated at the static proteome level and found that regulators of endo-lysosomal sorting, mRNA processing and components of the translation machinery remained low. These proteins included autophagy-related protein 9A (ATG9A) and translational stability regulator YTH N6-ethyladenosine RNA binding protein 3 (YTHDF3). Notably, 77% of the affected proteins in sporadic patients were also repressed in LRRK2-G2019S patients (False discovery rate (FDR) < 0.05) in both sporadic and LRRK2-G2019S samples. This analysis of nascent proteomes from PD patient skin cells reveals that regulators of proteostasis are repressed in both sporadic and LRRK2-G2019S PD. |
| first_indexed | 2024-03-09T07:29:24Z |
| format | Article |
| id | doaj.art-8d8e4f3ab7c54ff9ad886659c6cbd6f3 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-09T07:29:24Z |
| publishDate | 2023-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-8d8e4f3ab7c54ff9ad886659c6cbd6f32023-12-03T06:45:44ZengNature Portfolionpj Parkinson's Disease2373-80572023-02-019111310.1038/s41531-023-00460-wRegulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s diseaseDani Flinkman0Ye Hong1Jelena Gnjatovic2Prasannakumar Deshpande3Zsuzsanna Ortutay4Sirkku Peltonen5Valtteri Kaasinen6Peter James7Eleanor Coffey8Turku Bioscience Centre, University of Turku and Åbo Akademi UniversityTurku Bioscience Centre, University of Turku and Åbo Akademi UniversityTurku Bioscience Centre, University of Turku and Åbo Akademi UniversityTurku Bioscience Centre, University of Turku and Åbo Akademi UniversityTurku Bioscience Centre, University of Turku and Åbo Akademi UniversityDepartment of Dermatology, University of Turku and Turku University Turku University HospitalClinical Neurosciences, Faculty of Medicine, University of TurkuTurku Bioscience Centre, University of Turku and Åbo Akademi UniversityTurku Bioscience Centre, University of Turku and Åbo Akademi UniversityAbstract Deficits in protein synthesis are associated with Parkinson’s disease (PD). However, it is not known which proteins are affected or if there are synthesis differences between patients with sporadic and Leucine-Rich Repeat Kinase 2 (LRRK2) G2019S PD, the most common monogenic form. Here we used bio-orthogonal non-canonical amino acid tagging for global analysis of newly translated proteins in fibroblasts from sporadic and LRKK2-G2019S patients. Quantitative proteomic analysis revealed that several nascent proteins were reduced in PD samples compared to healthy without any significant change in mRNA levels. Using targeted proteomics, we validated which of these proteins remained dysregulated at the static proteome level and found that regulators of endo-lysosomal sorting, mRNA processing and components of the translation machinery remained low. These proteins included autophagy-related protein 9A (ATG9A) and translational stability regulator YTH N6-ethyladenosine RNA binding protein 3 (YTHDF3). Notably, 77% of the affected proteins in sporadic patients were also repressed in LRRK2-G2019S patients (False discovery rate (FDR) < 0.05) in both sporadic and LRRK2-G2019S samples. This analysis of nascent proteomes from PD patient skin cells reveals that regulators of proteostasis are repressed in both sporadic and LRRK2-G2019S PD.https://doi.org/10.1038/s41531-023-00460-w |
| spellingShingle | Dani Flinkman Ye Hong Jelena Gnjatovic Prasannakumar Deshpande Zsuzsanna Ortutay Sirkku Peltonen Valtteri Kaasinen Peter James Eleanor Coffey Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease npj Parkinson's Disease |
| title | Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease |
| title_full | Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease |
| title_fullStr | Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease |
| title_full_unstemmed | Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease |
| title_short | Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease |
| title_sort | regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and lrrk2 g2019s parkinson s disease |
| url | https://doi.org/10.1038/s41531-023-00460-w |
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