title: (Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation.
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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Fabienne C
authors.initials: FC
authors.lastname: Fiesel
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Ando
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Hudec
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Anneliese R
authors.initials: AR
authors.lastname: Hill
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Castanedes-Casey
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Caulfield
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Elisabeth L
authors.initials: EL
authors.lastname: Moussaud-Lamodière
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Jeannette N
authors.initials: JN
authors.lastname: Stankowski
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Peter O
authors.initials: PO
authors.lastname: Bauer
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Lorenzo-Betancor
authors.affiliation: 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.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Department of Neurology, Parkinson's and Movement Disorders Unit, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Arbelo
authors.affiliation: Department of Neurology, School of Medicine in Katowice Medical University of Silesia, Katowice, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Siuda
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: 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.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA Neurobiology of Disease, Mayo Graduate School, Jacksonville, FL, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA Neurobiology of Disease, Mayo Graduate School, Jacksonville, FL, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA Neurobiology of Disease, Mayo Graduate School, Jacksonville, FL, USA springer.wolfdieter@mayo.edu.
authors.forename: Wolfdieter
authors.initials: W
authors.lastname: Springer
mesh_terms: D000818:Animals; D000906:Antibodies; D015415:Biomarkers; D001921:Brain / Q000166:cytology; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D063306:Mitophagy / Q000235:genetics; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000906:Antibodies; D015415:Biomarkers; D011494:Protein Kinases; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: PINK1; Parkin; early‐onset Parkinson's disease; mitophagy; phosphorylated ubiquitin