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Cited by 185Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyUbiquitin and proteasome pathways

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(Patho‐)physiological relevance of PINK1‐dependent ubiquitin phosphorylation

Open access
Fiesel, Fabienne C, Ando, Maya, Hudec, Roman, Hill, Anneliese R, Castanedes‐Casey, Monica, Caulfield, Thomas R, Moussaud‐Lamodière, Elisabeth L, Stankowski, Jeannette N, Bauer, Peter O, Lorenzo‐Betancor, Oswaldo, Ferrer, Isidre, Arbelo, José M, Siuda, Joanna, Chen, Li, Dawson, Valina L, Dawson, Ted M, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Springer, Wolfdieter·2015·The EMBO Reports
DOI 10.15252/embr.201540514PMC PMC4576981
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Abstract

Mutations in PINK1 and PARKIN cause recessive, early-onset Parkinson's disease (PD). Together, these two proteins orchestrate a protective mitophagic response that ensures the safe disposal of damaged mitochondria. The kinase PINK1 phosphorylates ubiquitin (Ub) at the conserved residue S65, in addition to modifying the E3 ubiquitin ligase Parkin. The structural and functional consequences of Ub phosphorylation (pS65-Ub) have already been suggested from in vitro experiments, but its (patho-)physiological significance remains unknown. We have generated novel antibodies and assessed pS65-Ub signals in vitro and in cells, including primary neurons, under endogenous conditions. pS65-Ub is dependent on PINK1 kinase activity as confirmed in patient fibroblasts and postmortem brain samples harboring pathogenic mutations. We show that pS65-Ub is reversible and barely detectable under basal conditions, but rapidly induced upon mitochondrial stress in cells and amplified in the presence of functional Parkin. pS65-Ub accumulates in human brain during aging and disease in the form of cytoplasmic granules that partially overlap with mitochondrial, lysosomal, and total Ub markers. Additional studies are now warranted to further elucidate pS65-Ub functions and fully explore its potential for biomarker or therapeutic development.

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Metadata

Authors
Fiesel, F. C., Ando, M., Hudec, R., Hill, A. R., Castanedes‐Casey, M., Caulfield, T. R., Moussaud‐Lamodière, E. L., Stankowski, J. N., Bauer, P. O., Lorenzo‐Betancor, O., Ferrer, I., Arbelo, J. M., Siuda, J., Chen, L., Dawson, V. L., Dawson, T. M., Wszolek, Z. K., Ross, O. A., Dickson, D. W., & Springer, W.
Affiliations
  • Mayo Clinic (US)
  • Hospital Universitario Insular de Gran Canaria (ES)
  • Medical University of Silesia (PL)
  • Johns Hopkins University (US)
Corresponding author
Springer, Wolfdieter
ORCID
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2015-07-14
Volume
16
Issue
9
Pages
1114-1130
ISSN
  • 1469-221X (ISSN-L)
  • 1469-3178
DOI
10.15252/embr.201540514
PMC
PMC4576981
OpenAlex
W2102694693
Cited by
185
References
40
Citations by year
2026: 15 · 2025: 16 · 2024: 14 · 2023: 16 · 2022: 19 · 2021: 19 · 2020: 22 · 2019: 15 · 2018: 14 · 2017: 17 · 2016: 15 · 2015: 3
FWCI
11.52
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Reports (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Acceda (Universidad de Las Palmas de Gran Canaria) (submittedVersion)
Funders
  • NIH/NINDS (R01NS085070, R01NS078086)
  • Michael J. Fox Foundation for Parkinson's Research
  • Foundation for Mitochondrial Medicine
  • Mayo Clinic Foundation
  • Center for Individualized Medicine
  • Marriott Family Foundation
  • Gerstner Family Career Development Award
  • Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187)
  • NIH/NINDS Udall Center (P50 NS38377, MDSCRF 2007‐MSCRFI‐0420‐00, 2009‐MSCRFII‐0125‐00, MDSCRF 2012‐MSCRFII‐0268‐00, MDSCRF 2013‐MSCRFII‐0105‐00)
  • JPB Foundation
  • The Uehara Memorial Foundation
  • Mayo Clinic Center for Regenerative Medicine
  • ALS Association
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
PINK1, ubiquitin phosphorylation, Parkin, Parkinson's disease, mitophagy, mitochondrial stress, E3 ubiquitin ligase, ubiquitin, aging, biomarkers, primary neurons
MeSH terms
PTEN-Induced Putative Kinase, Animals, Antibodies, Brain, Fibroblasts, HeLa Cells, Humans, Mitochondria, Mutation, Neurons, Parkinson Disease, Phosphorylation, Protein Kinases, Biomarkers, Ubiquitin, Ubiquitin-Protein Ligases, Mice, Ubiquitination, Mitophagy

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