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

Flinkman, Dani LU ; Hong, Ye ; Gnjatovic, Jelena ; Deshpande, Prasannakumar ; Ortutay, Zsuzsanna ; Peltonen, Sirkku ; Kaasinen, Valtteri ; James, Peter LU orcid and Coffey, Eleanor (2023) In npj Parkinson's Disease 9(1).
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... (More)

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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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
npj Parkinson's Disease
volume
9
issue
1
article number
20
publisher
Springer Nature
external identifiers
  • pmid:36746972
  • scopus:85147513723
ISSN
2373-8057
DOI
10.1038/s41531-023-00460-w
language
English
LU publication?
yes
id
a7bedc9f-2ed9-424a-bdcf-468fce603a42
date added to LUP
2023-02-20 11:49:59
date last changed
2024-06-13 14:24:53
@article{a7bedc9f-2ed9-424a-bdcf-468fce603a42,
  abstract     = {{<p>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) &lt; 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.</p>}},
  author       = {{Flinkman, Dani and Hong, Ye and Gnjatovic, Jelena and Deshpande, Prasannakumar and Ortutay, Zsuzsanna and Peltonen, Sirkku and Kaasinen, Valtteri and James, Peter and Coffey, Eleanor}},
  issn         = {{2373-8057}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Springer Nature}},
  series       = {{npj Parkinson's Disease}},
  title        = {{Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease}},
  url          = {{http://dx.doi.org/10.1038/s41531-023-00460-w}},
  doi          = {{10.1038/s41531-023-00460-w}},
  volume       = {{9}},
  year         = {{2023}},
}