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Cited by 20Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingAutophagy in Disease and Therapy

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

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Flinkman, Dani, Hong, Ye, Gnjatovic, Jelena, Deshpande, Prasannakumar, Ortutay, Zsuzsanna, Peltonen, Sirkku, Kaasinen, Valtteri, James, Peter +1 more·2023·npj Parkinson's Disease
DOI 10.1038/s41531-023-00460-wPMC PMC9902458
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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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Authors
Flinkman, D., Hong, Y., Gnjatovic, J., Deshpande, P., Ortutay, Z., Peltonen, S., Kaasinen, V., James, P., & Coffey, E.
Affiliations
  • Åbo Akademi University (FI)
  • University of Turku (FI)
Corresponding author
Coffey, Eleanor
ORCID
Venue
npj Parkinson's Disease
Publisher
Springer Science and Business Media LLC
Published
2023-02-06
Volume
9
Issue
1
Pages
20-20
ISSN
2373-8057 (ISSN-L)
DOI
10.1038/s41531-023-00460-w
PMC
PMC9902458
OpenAlex
W4319334414
Cited by
20
References
77
Citations by year
2026: 3 · 2025: 7 · 2024: 9 · 2023: 1
FWCI
3.57
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Parkinson s Disease (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Åbo Akademi University Research Portal (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Åbo Akademi University University of Turku MATTI Doctoral Programme
  • Michael J. Fox Foundation for Parkinson’s Research
  • Business Finland
  • Business Finland Matti Graduate school
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Parkinson's disease, LRRK2 G2019S, sporadic Parkinson's disease, proteostasis, translation repression, nascent protein, fibroblasts, ATG9A, YTHDF3, mRNA processing, protein synthesis

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