Format

Send to

Choose Destination
EMBO Rep. 2015 Sep;16(9):1114-30. doi: 10.15252/embr.201540514. Epub 2015 Jul 10.

(Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation.

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
2
Institut de Neuropatologia, Servei d'Anatomia Patològica Hospital Universitari de Bellvitge, Hospitalet del Llobregat, Spain CIBERNED, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Barcelona, Spain.
3
Department of Neurology, Parkinson's and Movement Disorders Unit, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain.
4
Department of Neurology, School of Medicine in Katowice Medical University of Silesia, Katowice, Poland.
5
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA.
7
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
8
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
9
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA Neurobiology of Disease, Mayo Graduate School, Jacksonville, FL, USA.
10
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA Neurobiology of Disease, Mayo Graduate School, Jacksonville, FL, USA springer.wolfdieter@mayo.edu.

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.

KEYWORDS:

PINK1; Parkin; early‐onset Parkinson's disease; mitophagy; phosphorylated ubiquitin

PMID:
26162776
PMCID:
PMC4576981
DOI:
10.15252/embr.201540514
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center