Regulators of Proteostasis Are Translationally Repressed in Fibroblasts from Patients with Sporadic and LRRK2-G2019S Parkinson's Disease

Overview

Journal NPJ Parkinsons Dis

Date 2023 Feb 6

PMID 36746972

Authors

Dani Flinkman

Ye Hong

Jelena Gnjatovic

Prasannakumar Deshpande

Zsuzsanna Ortutay

Sirkku Peltonen

Valtteri Kaasinen

Peter James

Eleanor Coffey

Affiliations

Soon will be listed here.

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.

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