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

被引:134
作者
Fiesel, Fabienne C. [1 ]
Ando, Maya [1 ]
Hudec, Roman [1 ]
Hill, Anneliese R. [1 ]
Castanedes-Casey, Monica [1 ]
Caulfield, Thomas R. [1 ]
Moussaud-Lamodiere, Elisabeth L. [1 ]
Stankowski, Jeannette N. [1 ]
Bauer, Peter O. [1 ]
Lorenzo-Betancor, Oswaldo [1 ]
Ferrer, Isidre [2 ,3 ]
Arbelo, Jose M. [4 ]
Siuda, Joanna [5 ]
Chen, Li [6 ,7 ]
Dawson, Valina L. [6 ,7 ,8 ,9 ,10 ]
Dawson, Ted M. [6 ,7 ,9 ,10 ,11 ,12 ]
Wszolek, Zbigniew K. [13 ]
Ross, Owen A. [1 ,14 ]
Dickson, Dennis W. [1 ,14 ]
Springer, Wolfdieter [1 ,14 ]
机构
[1] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
[2] Hosp Univ Bellvitge, Inst Neuropatol, Serv Anat Patol, Hosp Del Llobregat, Spain
[3] Inst Salud Carlos III, CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenrat, Barcelona, Spain
[4] Hosp Univ Insular Gran Canaria, Parkinsons & Movement Disorders Unit, Dept Neurol, Las Palmas Gran Canaria, Spain
[5] Med Univ Silesia, Sch Med, Dept Neurol, Katowice, Poland
[6] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat & Stem Cell Programs, Baltimore, MD 21205 USA
[7] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA
[8] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA
[9] Adrienne Helis Malvin Med Res Fdn, New Orleans, LA USA
[10] Diana Helis Henry Med Res Fdn, New Orleans, LA USA
[11] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA
[12] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA
[13] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA
[14] Mayo Grad Sch, Neurobiol Dis, Jacksonville, FL USA
关键词
early-onset Parkinson's disease; mitophagy; Parkin; phosphorylated ubiquitin; PINK1; PARKIN TRANSLOCATION; PINK1; CHAIN; MITOPHAGY; ACTIVATION; REVEAL;
D O I
10.15252/embr.201540514
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 invitro experiments, but its (patho-)physiological significance remains unknown. We have generated novel antibodies and assessed pS65-Ub signals invitro 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.
引用
收藏
页码:1114 / 1130
页数:17
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