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Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease

Authors :
Dani Flinkman
Ye Hong
Jelena Gnjatovic
Prasannakumar Deshpande
Zsuzsanna Ortutay
Sirkku Peltonen
Valtteri Kaasinen
Peter James
Eleanor Coffey
Source :
npj Parkinson's Disease, Vol 9, Iss 1, Pp 1-13 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

Abstract

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)

Details

Language :
English
ISSN :
23738057
Volume :
9
Issue :
1
Database :
Directory of Open Access Journals
Journal :
npj Parkinson's Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.8d8e4f3ab7c54ff9ad886659c6cbd6f3
Document Type :
article
Full Text :
https://doi.org/10.1038/s41531-023-00460-w