(Patho‐)physiological relevance of PINK1‐dependent ubiquitin phosphorylation
Open accessAbstract
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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pS65-Ub accumulates during aging, stress, and disease.
“pS65-Ub has been shown to accumulate during aging, stress, and disease [13, 14]”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [13]
pUbS65 accumulates with mitochondrial stress, age, and disease and serves as a specific signal for recognition by autophagy receptors.
“Moreover, pUbS65 has been suggested to accumulate with mitochondrial stress, age, and disease [19] and to serve as a specific signal for recognition by autophagy receptors [20, 21].”
From miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1) (2016) · cites this paper as [19]
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PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Geisler, S., Holmström, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J., & Springer, W. (2010) · Nature Cell Biology · doi:10.1038/ncb2012 · Cited by 2,835 · see citing works
Self-citationThe Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease
Pickrell, A. M., & Youle, R. J. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.007 · Cited by 2,310 · see citing works
Shiba-Fukushima, K., Imai, Y., Yoshida, S., Ishihama, Y., Kanao, T., Sato, S., & Hattori, N. (2012) · Scientific Reports · doi:10.1038/srep01002 · Cited by 577 · see citing works
Direct Conversion of Fibroblasts to Neurons by Reprogramming PTB-Regulated MicroRNA Circuits
Xue, Y., Ouyang, K., Huang, J., Zhou, Y., Ouyang, H., Li, H., Wang, G., Wu, Q., Wei, C., Bi, Y., et al. (2013) · Cell · doi:10.1016/j.cell.2012.11.045 · Cited by 562 · see citing works
Parkin-catalyzed Ubiquitin-Ester Transfer Is Triggered by PINK1-dependent Phosphorylation
Iguchi, M., Kujuro, Y., Okatsu, K., Koyano, F., Kosako, H., Kimura, M., Suzuki, N., Uchiyama, S., Tanaka, K., & Matsuda, N. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.467530 · Cited by 209 · see citing works
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Research works printed but not linked: 38
- Scarffe LA, Stevens DA, Dawson VL, Dawson TM. Parkin and PINK1: much more than mitophagy. Trends Neurosci. 2014;37:315–324. doi: 10.1016/j.tins.2014.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG, Gourlay R, Burchell L, Walden H, Macartney TJ, Deak M, et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol. 2012;2:120080. doi: 10.1098/rsob.120080. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Caulfield TR, Fiesel FC, Moussaud-Lamodiere EL, Dourado DF, Flores SC, Springer W. Phosphorylation by PINK1 releases the UBL domain and initializes the conformational opening of the E3 ubiquitin ligase Parkin. PLoS Comput Biol. 2014;10:e1003935. doi: 10.1371/journal.pcbi.1003935. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y. PINK1-mediated phosphorylation of Parkin boosts Parkin activity in Drosophila. PLoS Genet. 2014b;10:e1004391. doi: 10.1371/journal.pgen.1004391. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Fiesel FC, Moussaud-Lamodiere EL, Ando M, Springer W. A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. J Cell Sci. 2014;127:3488–3504. doi: 10.1242/jcs.147520. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Kazlauskaite A, Kelly V, Johnson C, Baillie C, Hastie CJ, Peggie M, Macartney T, Woodroof HI, Alessi DR, Pedrioli PG, et al. Phosphorylation of Parkin at Serine65 is essential for activation: elaboration of a Miro1 substrate-based assay of Parkin E3 ligase activity. Open Biol. 2014a;4:130213. doi: 10.1098/rsob.130213. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Dikic I, Bremm A. DUBs counteract parkin for efficient mitophagy. EMBO J. 2014;33:2442–2443. doi: 10.15252/embj.201490101. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol. 2014;205:143–153. doi: 10.1083/jcb.201402104. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, Alessi DR, Knebel A, Trost M, Muqit MM. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J. 2014b;460:127–139. doi: 10.1042/BJ20140334. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, Kimura Y, Tsuchiya H, Yoshihara H, Hirokawa T, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014;510:162–166. doi: 10.1038/nature13392. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- Ordureau A, Sarraf SA, Duda DM, Heo JM, Jedrychowski MP, Sviderskiy VO, Olszewski JL, Koerber JT, Xie T, Beausoleil SA, et al. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell. 2014;56:360–375. doi: 10.1016/j.molcel.2014.09.007. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N, Imai Y. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet. 2014a;10:e1004861. doi: 10.1371/journal.pgen.1004861. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Zhang C, Lee S, Peng Y, Bunker E, Giaime E, Shen J, Zhou Z, Liu X. PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions. Curr Biol. 2014;24:1854–1865. doi: 10.1016/j.cub.2014.07.014. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Wauer T, Swatek KN, Wagstaff JL, Gladkova C, Pruneda JN, Michel MA, Gersch M, Johnson CM, Freund SM, Komander D. Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis. EMBO J. 2014;34:307–325. doi: 10.15252/embj.201489847. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Okatsu K, Koyano F, Kimura M, Kosako H, Saeki Y, Tanaka K, Matsuda N. Phosphorylated ubiquitin chain is the genuine Parkin receptor. J Cell Biol. 2015;209:111–128. doi: 10.1083/jcb.201410050. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Siuda J, Jasinska-Myga B, Boczarska-Jedynak M, Opala G, Fiesel FC, Moussaud-Lamodiere EL, Scarffe LA, Dawson VL, Ross OA, Springer W, et al. Early-onset Parkinson’s disease due to PINK1 p. Q456X mutation–clinical and functional study. Parkinsonism Relat Disord. 2014;20:1274–1278. doi: 10.1016/j.parkreldis.2014.08.019. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang WY, Fostvedt E, Jansen-West K, Belzil VV, Desaro P, et al. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron. 2014;83:1043–1050. doi: 10.1016/j.neuron.2014.07.041. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Samaranch L, Lorenzo-Betancor O, Arbelo JM, Ferrer I, Lorenzo E, Irigoyen J, Pastor MA, Marrero C, Isla C, Herrera-Henriquez J, et al. PINK1-linked parkinsonism is associated with Lewy body pathology. Brain. 2010;133:1128–1142. doi: 10.1093/brain/awq051. [DOI] [PubMed] [Google Scholar] · DOI
- Riley BE, Olzmann JA. A polyubiquitin chain reaction: parkin recruitment to damaged mitochondria. PLoS Genet. 2015;11:e1004952. doi: 10.1371/journal.pgen.1004952. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Lu W, Karuppagounder SS, Springer DA, Allen MD, Zheng L, Chao B, Zhang Y, Dawson VL, Dawson TM, Lenardo M. Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder. Nat Commun. 2014;5:4930. doi: 10.1038/ncomms5930. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Imai Y, Kanao T, Sawada T, Kobayashi Y, Moriwaki Y, Ishida Y, Takeda K, Ichijo H, Lu B, Takahashi R. The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila. PLoS Genet. 2010;6:e1001229. doi: 10.1371/journal.pgen.1001229. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Palikaras K, Tavernarakis N. Mitophagy in neurodegeneration and aging. Front Genet. 2012;3:297. doi: 10.3389/fgene.2012.00297. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Zhang YJ, Caulfield T, Xu YF, Gendron TF, Hubbard J, Stetler C, Sasaguri H, Whitelaw EC, Cai S, Lee WC, et al. The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation. Hum Mol Genet. 2013;22:3112–3122. doi: 10.1093/hmg/ddt166. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Cai Q, Zakaria HM, Simone A, Sheng ZH. Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons. Curr Biol. 2012;22:545–552. doi: 10.1016/j.cub.2012.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Lin WL, Castanedes-Casey M, Dickson DW. Transactivation response DNA-binding protein 43 microvasculopathy in frontotemporal degeneration and familial Lewy body disease. J Neuropathol Exp Neurol. 2009;68:1167–1176. doi: 10.1097/NEN.0b013e3181baacec. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Weeks SD, Grasty KC, Hernandez-Cuebas L, Loll PJ. Crystal structures of Lys-63-linked tri- and di-ubiquitin reveal a highly extended chain architecture. Proteins. 2009;77:753–759. doi: 10.1002/prot.22568. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Zhang N, Wang Q, Ehlinger A, Randles L, Lary JW, Kang Y, Haririnia A, Storaska AJ, Cole JL, Fushman D, et al. Structure of the s5a:k48-linked diubiquitin complex and its interactions with rpn13. Mol Cell. 2009;35:280–290. doi: 10.1016/j.molcel.2009.06.010. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Jacobson MP, Friesner RA, Xiang Z, Honig B. On the role of the crystal environment in determining protein side-chain conformations. J Mol Biol. 2002;320:597–608. doi: 10.1016/s0022-2836(02)00470-9. [DOI] [PubMed] [Google Scholar] · DOI
- Krieger E, Joo K, Lee J, Raman S, Thompson J, Tyka M, Baker D, Karplus K. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: four approaches that performed well in CASP8. Proteins. 2009;77(Suppl 9):114–122. doi: 10.1002/prot.22570. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst. 1993;26:283–291. [Google Scholar]
- Joosten RP, Salzemann J, Bloch V, Stockinger H, Berglund AC, Blanchet C, Bongcam-Rudloff E, Combet C, Da Costa AL, Deleage G, et al. PDB_REDO: automated re-refinement of X-ray structure models in the PDB. J Appl Crystallogr. 2009;42:376–384. doi: 10.1107/S0021889809008784. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Krieger E, Nabuurs SB, Vriend G. Homology modeling. Methods Biochem Anal. 2003;44:509–523. doi: 10.1002/0471721204.ch25. [DOI] [PubMed] [Google Scholar] · DOI
- Vriend G. WHAT IF: a molecular modeling and drug design program. J Mol Graph. 1990;8:52–56. doi: 10.1016/0263-7855(90)80070-v. 29. [DOI] [PubMed] [Google Scholar] · DOI
- Caulfield TR, Devkota B, Rollins GC. Examinations of tRNA Range of Motion Using Simulations of Cryo-EM Microscopy and X-Ray Data. J Biophys. 2011;2011:219515. doi: 10.1155/2011/219515. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Krieger E, Dunbrack RL, Jr, Hooft RW, Krieger B. Assignment of protonation states in proteins and ligands: combining pKa prediction with hydrogen bonding network optimization. Methods Mol Biol. 2012;819:405–421. doi: 10.1007/978-1-61779-465-0_25. [DOI] [PubMed] [Google Scholar] · DOI
- Schrödinger. Maestro. New York, NY: Schrödinger, LLC; 2010. version 9.1. [Google Scholar]
- Schrödinger. Suite 2012. New York, NY: Schrödinger, LLC; 2012. [Google Scholar]
- Schrödinger. Biologics Suite: BioLuminate. New York, NY: Schrödinger, LLC; 2013. version 1.1. [Google Scholar]
Cited by
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Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
“have very recently been described as novel tools to detect the activation of PINK1-PARK2-mediated mitophagy.(744) p-S65-”
Self-citationKlionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
Self-citationSwatek, K. N., & Komander, D. (2016) · Cell Research · doi:10.1038/cr.2016.39 · Cited by 2,070 · see citing works
Deciphering the Molecular Signals of PINK1/Parkin Mitophagy
Nguyen, T. N., Padman, B. S., & Lazarou, M. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.05.008 · Cited by 732 · see citing works
Building and decoding ubiquitin chains for mitophagy
Harper, J. W., Ordureau, A., & Heo, J. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.129 · Cited by 668 · see citing works
Mitophagy in human health, ageing and disease
Picca, A., Faitg, J., Auwerx, J., Ferrucci, L., & D’Amico, D. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00930-8 · Cited by 635 · see citing works
“In healthy older adults, p-Ub proteins have been shown to accumulate in the hippocampus, often within vacuoles, while only a few p-Ub granules were detected in younger individuals 74 .”
Mitochondrial dysfunction and mitophagy in parkinson’s disease: from mechanism to therapy
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PINK1/PARKIN signalling in neurodegeneration and neuroinflammation
Quinn, P. M. J., Moreira, P. I., Ambrósio, A. F., & Alves, C. H. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01062-w · Cited by 486 · see citing works
Autophagy in Parkinson's Disease
Hou, X., Watzlawik, J. O., Fiesel, F. C., & Springer, W. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.01.037 · Cited by 355 · see citing works
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BackgroundResultSelf-citationPINK1 and Parkin: emerging themes in mitochondrial homeostasis.
McWilliams, T. G., & Muqit, M. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.03.013 · Cited by 315 · see citing works
“A wave of mitophagy was observed in late embryonic mito-QC mice, suggesting that a defined window of developmental cardiomitophagy in utero may orchestrate an essential phase of metabolic adaption during early life [33].”
Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond
Bingol, B., & Sheng, M. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.015 · Cited by 333 · see citing works
PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol
Sekine, S., & Youle, R. J. (2018) · BMC Biology · doi:10.1186/s12915-017-0470-7 · Cited by 308 · see citing works
“creased in brain samples of patients harboring pathogenic PD mutations [80].”
BackgroundLópez‐Doménech, G., Howden, J. H., Covill‐Cooke, C., Morfill, C., Patel, J. V., Bürli, R. W., Crowther, D. C., Birsa, N., Brandon, N. J., & Kittler, J. T. (2021) · The EMBO Journal · doi:10.15252/embj.2018100715 · Cited by 80 · see citing works
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Mitochondrial quality control in health and in Parkinson’s disease
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Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila
Cornelissen, T., Vilain, S., Vints, K., Gounko, N., Verstreken, P., & Vandenberghe, W. (2018) · eLife · doi:10.7554/elife.35878 · Cited by 239 · see citing works
“Consistent with this, pS65-Ub, a readout of PINK1 activity, is almost undetectable in postmortem brains from neurologically normal, young human subjects, but accumulates in brains from elderly individuals (Fiesel et al., 2015).”
BackgroundTruban, D., Hou, X., Caulfield, T. R., Fiesel, F. C., & Springer, W. (2016) · Journal of Parkinson’s Disease · doi:10.3233/jpd-160989 · Cited by 237 · see citing works
“In summary, numerous molecules and cellular processes appear to impact PINK1/Parkin, the mitochondrial quality control as well as several other PD genes.”
BackgroundSelf-citationMitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases
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Yamano, K., Matsuda, N., & Tanaka, K. (2016) · EMBO Reports · doi:10.15252/embr.201541486 · Cited by 239 · see citing works
“Therefore, this can be used as a potential biomarker for PD [177].”
Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases
Chu, C. T. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.015 · Cited by 218 · see citing works
Expanding the ubiquitin code through post‐translational modification
Herhaus, L., & Đikić, I. (2015) · EMBO Reports · doi:10.15252/embr.201540891 · Cited by 230 · see citing works
Picca, A., Guerra, F., Calvani, R., Romano, R., Coelho-Júnior, H. J., Bucci, C., & Marzetti, E. (2021) · Biomolecules · doi:10.3390/biom11101508 · Cited by 189 · see citing works
PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival
Lee, Y., Stevens, D. A., Kang, S.-U., Jiang, H., Lee, Y.-I., Ko, H. S., Scarffe, L. A., Umanah, G. K. E., Kang, H., Ham, S., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.090 · Cited by 207 · see citing works
Self-citationThe RING finger protein family in health and disease
Cai, C., Tang, Y., Zhai, J., & Zheng, C. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01152-2 · Cited by 194 · see citing works
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Barodia, S. K., Creed, R. B., & Goldberg, M. S. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.12.004 · Cited by 168 · see citing works
“…Kazlauskaite et al. 2014b; Koyano et al. 2014; Ordureau 8 et al. 2014; Sauve and Gehring 2014; Shiba-Fukushima et al. 2014; Caulfield et al. 2015; Fiesel et al. 2015a; Kazlauskaite et al. 2015; Okatsu et al. 2015a; Okatsu et al. 2015b; Ordureau et al. 2015a; Ordureau et al. 2015b; Wauer et al.…”
BackgroundInfluentialKim, J., Fiesel, F. C., Belmonte, K. C., Hudec, R., Wang, W.-X., Kim, C., Nelson, P. T., Springer, W., & Kim, J. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0121-4 · Cited by 163 · see citing works
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Malik, B. R., Maddison, D. C., Smith, G. A., & Peters, O. M. (2019) · Molecular Brain · doi:10.1186/s13041-019-0504-x · Cited by 180 · see citing works
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BackgroundThe genetic architecture of mitochondrial dysfunction in Parkinson’s disease
Larsen, S. B., Hanss, Z., & Krüger, R. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2768-8 · Cited by 181 · see citing works
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Esmaeili, Y., Yarjanli, Z., Paknia, F., Bidram, E., Łoś, M., Eshraghi, M., Klionsky, D. J., Ghavami, S., & Zarrabi, A. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.03.001 · Cited by 180 · see citing works
The Function of Autophagy in Neurodegenerative Diseases
Kiriyama, Y., & Nochi, H. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161125990 · Cited by 168 · see citing works
Hou, X., Fiesel, F. C., Truban, D., Castanedes Casey, M., Lin, W.-L., Soto, A. I., Tacik, P., Rousseau, L. G., Diehl, N. N., Heckman, M. G., et al. (2018) · Autophagy · doi:10.1080/15548627.2018.1461294 · Cited by 147 · see citing works
“For comparing different antibodies in the detection of peptide, N-terminal biotinylated p-S65-Ub (custom-made at Thinkpeptides) [25] was run on the gel at serial dilution from 10–500 ng and detected with 0.75 µg/ml p-S65Ub antibodies (in-house [25] or Millipore Sigma, ABS1513).”
BackgroundMethodInfluentialSelf-citationAutophagy in neurodegeneration: New insights underpinning therapy for neurological diseases
Corti, O., Blomgren, K., Poletti, A., & Beart, P. M. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15002 · Cited by 141 · see citing works
“All rights reserved phosphorylated ubiquitin partially colocalizing with mitochondria and lysosomes in the aged and PDaffected human brain, but it remains to be clarified whether this reflects impaired or increased mitophagy (Fiesel et al., 2015).”
BackgroundHeterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism
Puschmann, A., Fiesel, F. C., Caulfield, T. R., Hudec, R., Ando, M., Fričová, D., Hou, X., Ogaki, K., Heckman, M. G., James, E. D., et al. (2016) · Brain · doi:10.1093/brain/aww261 · Cited by 137 · see citing works
“Rabbit anti-p-Ser65-Ub (1:5000 for WB, 1:250–500 for IF, and 1:250 for MSD) has been described recently (Fiesel et al., 2015a).”
BackgroundMethodResultInfluentialSelf-citationLis, P., Burel, S., Steger, M., Mann, M., Brown, F., Diez, F., Tonelli, F., Holton, J., Ho, P. W., Ho, S., et al. (2017) · Biochemical Journal · doi:10.1042/bcj20170802 · Cited by 131 · see citing works
“This strategy was selected to maximise peptide exposure in both possible conjugation orientations and was previously adopted to generate sensitive antibodies recognising PINK1 phosphorylated ubiquitin [28].”
MethodOh, C.-K., Sultan, A., Platzer, J., Dolatabadi, N., Soldner, F., McClatchy, D. B., Diedrich, J. K., Yates, J. R., Ambasudhan, R., Nakamura, T., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.068 · Cited by 133 · see citing works
“Consistent with a reduction in PINK1 kinase activity, phosphorylated poly-ubiquitin chains were also decreased by non-nitrosylatable PINK1 (Figures 2F and 2G) (Fiesel et al., 2015).”
BackgroundDirect neuronal reprogramming: Fast forward from new concepts toward therapeutic approaches
Bocchi, R., Masserdotti, G., & Götz, M. (2021) · Neuron · doi:10.1016/j.neuron.2021.11.023 · Cited by 128 · see citing works
Miller, S., & Muqit, M. M. K. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.029 · Cited by 129 · see citing works
“As a direct measure of PINK1 and Parkin activity, pS65-Ub is a promising biomarker [23,27].”
BackgroundPatrick, K. L., Bell, S. L., Weindel, C. G., & Watson, R. O. (2019) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2019.00138 · Cited by 110 · see citing works
“However, PINK1 and Parkin also have regulatory roles in the biogenesis of mitochondria via PARIS and PGC1-alpha, so mutations in PINK1 or PARK2 could contribute to mitochondrial dysfunction by preventing the replacement of mitochondria (Fiesel et al., 2015).”
BackgroundMechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond
Bayne, A. N., & Trempe, J. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03203-4 · Cited by 113 · see citing works
Intra- and Intercellular Quality Control Mechanisms of Mitochondria
Kiriyama, Y., & Nochi, H. (2017) · Cells · doi:10.3390/cells7010001 · Cited by 128 · see citing works
Ren, H., Zhai, W., Lu, X., & Wang, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.691881 · Cited by 101 · see citing works
Mitophagy and reactive oxygen species interplay in Parkinson’s disease
Xiao, B., Kuruvilla, J., & Tan, E. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00402-y · Cited by 112 · see citing works
Agarwal, S., & Muqit, M. M. K. (2021) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2021.09.005 · Cited by 103 · see citing works
Parkin Regulation and Neurodegenerative Disorders
Zhang, C., Hang, L., Yao, T., & Lim, K. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00248 · Cited by 82 · see citing works
“At the same time, they also suggest therapeutic directions in managing the disease.”
BackgroundInfluentialMechanisms, pathophysiological roles and methods for analyzing mitophagy – recent insights
Williams, J. A. R., & Ding, W. (2017) · Biological Chemistry · doi:10.1515/hsz-2017-0228 · Cited by 89 · see citing works
“Under basal conditions, p-Serine65-UB has low detection levels, but it is induced during mitochondrial stress and is further increased in the presence of Parkin in cells and primary neurons (Fiesel et al., 2015).”
BackgroundDisruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease
Vizziello, M., Borellini, L., Franco, G., & Ardolino, G. (2021) · Cells · doi:10.3390/cells10113022 · Cited by 98 · see citing works
“Ubiquitin phosphorylated at Ser65-which can be considered as a biomarker of PINK1 activity-accumulates in brains from elderly human subjects [95], and mice with defective mitochondrial DNA proofreading [96], suggesting that PINK1-mediated mitophagy is induced by both aging and accumulation of mitochondrial damage.”
BackgroundThe PINK1 p.I368N mutation affects protein stability and ubiquitin kinase activity
Ando, M., Fiesel, F. C., Hudec, R., Caulfield, T. R., Ogaki, K., Górka-Skoczylas, P., Koziorowski, D., Friedman, A., Chen, L., Dawson, V. L., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0174-z · Cited by 79 · see citing works
“HSP90 (WB, 1:2,000, 610419, BD), mouse anti-FLAG (WB, 1:150,000, F3165, Sigma Aldrich), mouse antiGAPDH (WB, 1:150,000, H86504M, Meridian Life science), mouse anti-Mitofusin 1 (WB, 1:5,000, ab57602, Abcam), rabbit anti-p38 MAPK (WB, 1:1,000, #9212, Cell Signaling), rabbit anti-PINK1 (WB, 1:2,000, BC100494, Novus Biolo…”
BackgroundMethodInfluentialSelf-citationChuang, K.-C., Chang, C., Chang, S.-H., Huang, S., Chuang, S., Li, Z., Wang, S.-T., Kao, J., Chen, Y., & Shieh, J. (2020) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2020.03.009 · Cited by 81 · see citing works
Fiesel, F. C., James, E. D., Hudec, R., & Springer, W. (2017) · Oncotarget · doi:10.18632/oncotarget.22287 · Cited by 67 · see citing works
“The following antibodies have been used for western blot (WB) or immunofluorescence (IF): beta III tubulin (#5568, CST, WB: 1/2,000 or AB9354, Millipore, IF: 1/250), FLAG (F3165, Sigma, WB: 1/150,000), GAPDH (H86504M, Meridian Life Sciences, WB: 1/500,000), LC3B (NB100-2220, Novus Biologicals, WB: 1/5,000), Miro1 (H00…”
BackgroundMethodInfluentialSelf-citationHou, X., Watzlawik, J. O., Cook, C. N., Liu, C., Kang, S. S., Lin, W., Deture, M. A., Heckman, M. G., Diehl, N. N., Al‐Shaikh, F. S. H., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12198 · Cited by 72 · see citing works
Self-citationNicoletti, V., Palermo, G., Prete, E. D., Mancuso, M., & Ceravolo, R. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.636506 · Cited by 72 · see citing works
Ubiquitin and Parkinson's disease through the looking glass of genetics
Walden, H., & Muqit, M. M. K. (2017) · Biochemical Journal · doi:10.1042/bcj20160498 · Cited by 67 · see citing works
Brahmachari, S., Lee, S., Kim, S., Yuan, C.-Q., Karuppagounder, S. S., Ge, P., Shi, R., Kim, E. J., Liu, A. C. H., Kim, D., et al. (2019) · Brain : a journal of neurology · doi:10.1093/brain/awz172 · Cited by 62 · see citing works
Self-citationParadoxical Mitophagy Regulation by PINK1 and TUFm
Lin, J., Chen, K., Chen, W., Yao, Y., Ni, S., Ye, M., Zhuang, G., Hu, M., Gao, J., Gao, C., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.10.007 · Cited by 61 · see citing works
Watzlawik, J. O., Hou, X., Fričová, D., Ramnarine, C., Barodia, S. K., Gendron, T. F., Heckman, M. G., Deture, M. A., Siuda, J. S., Wszołek, Z. K., et al. (2020) · Autophagy · doi:10.1080/15548627.2020.1834712 · Cited by 56 · see citing works
Self-citationEvidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson’s disease
Shiba‐Fukushima, K., Ishikawa, K., Inoshita, T., Izawa, N., Takanashi, M., Sato, S., Onodera, O., Akamatsu, W., Okano, H., Imai, Y., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx201 · Cited by 62 · see citing works
“The absence of phospho-Ub signals has been reported in fibroblasts, induced pluripotent stem cell (iPSC)-derived neurons and human brain tissues from PINK1 patients, whereas phospho-Ub signals were shown to accumulate in human brain tissues from older subjects and in PD and amyotrophic lateral sclerosis patients (28),…”
Hexokinases link DJ-1 to the PINK1/parkin pathway
Hauser, D., Mamais, A., Conti, M., Primiani, C., Kumaran, R., Dillman, A., Langston, R., Beilina, A., Garcia, J. H., Díaz-Ruiz, A., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0212-x · Cited by 55 · see citing works
“Immunocytochemistry using a rabbit polyclonal antibody raised against pS65-ubiquitin (1:1000) [42] was performed as described above (Alexa Fluor 647 donkey anti-rabbit IgG, 1:500).”
MethodSelf-citationDrouin‐Ouellet, J., Pircs, K., Barker, R. A., Jakobsson, J., & Parmar, M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00530 · Cited by 54 · see citing works
“…the reprogramming construct(s) (Liu et al., 2014; Su et al., 2014; Bavamian et al., 2015; Lim et al., 2016a) or based on the expression of neuronal markers such as TUJ1 (βIII-Tubulin) (Iovino et al., 2014; Liu et al., 2014; Fiesel et al., 2015; Lim et al., 2016a,b; Puschmann et al., 2017).”
BackgroundUSP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons
Okarmus, J., Agergaard, J. B., Stummann, T. C., Haukedal, H., Ambjørn, M., Freude, K., Fog, K., & Meyer, M. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06439-6 · Cited by 61 · see citing works
Structural Mechanisms of Mitochondrial Quality Control Mediated by PINK1 and Parkin
Trempe, J., & Gehring, K. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168090 · Cited by 58 · see citing works
PINK1 phosphorylates ubiquitin predominantly in astrocytes
Barodia, S. K., McMeekin, L. J., Creed, R. B., Quinones, E. K., Cowell, R. M., & Goldberg, M. S. (2019) · npj Parkinson s Disease · doi:10.1038/s41531-019-0101-9 · Cited by 50 · see citing works
“Because PINK1 is apparently the only kinase that phosphorylates ubiquitin, S65phosphorylated ubiquitin (pS65-ub) can be used as a measure of PINK1 activity.(4,5,9) Previous in vitro studies have demonstrated that depolarization of mitochondria with ionophores, such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP) o…”
BackgroundMethodActivation mechanisms of the E3 ubiquitin ligase parkin
Panicker, N., Dawson, V. L., & Dawson, T. M. (2017) · Biochemical Journal · doi:10.1042/bcj20170476 · Cited by 63 · see citing works
Self-citationUbiquitin S65 phosphorylation engenders a pH-sensitive conformational switch
Dong, X., Gong, Z., Lu, Y.-B., Liu, K., Qin, L., Ran, M.-L., Zhang, C.-L., Liu, Z., Zhang, W.-P., & Tang, C. (2017) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1705718114 · Cited by 47 · see citing works
“Upon oxidative stress, neurodegeneration, and aging, Ub phosphorylation level drastically increases (4, 8, 31), whereas mitophagy, apoptosis, ischemia, inflammation, aging, and many pathophysiological conditions are all associated with changes in cellular pH (32–35).”
BackgroundMultiple pathways for mitophagy: A neurodegenerative conundrum for Parkinson’s disease
Chu, C. T. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.04.004 · Cited by 49 · see citing works
“Human post-mortem studies indicate increased staining for phospho-ubiquitin in degenerating substantia nigra neurons [21], with a similar staining pattern to structures previously defined ultrastructurally as mitochondria within autophagosomes (mitophagosomes) in PD/LBD patients [85].”
BackgroundUbiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment
Chin, L., & Li, L. (2016) · Translational Neurodegeneration · doi:10.1186/s40035-015-0049-6 · Cited by 58 · see citing works
“The phospho-Ser65-ubiquitin-positive granules were partially co-localized with mitochondrial and lysosomal markers [83], suggesting that phosphoSer65-ubiquitin was accumulated in damaged mitochondria and/or in autolysosomes containing damaged mitochondria, perhaps as a result of increased mitochondrial damage and/or i…”
BackgroundInfluentialHow should we be using biomarkers in trials of disease modification in Parkinson’s disease?
Vijiaratnam, N., & Foltynie, T. (2023) · Brain · doi:10.1093/brain/awad265 · Cited by 56 · see citing works
“226,227 Investigations of this marker in biofluid samples will be of interest, possibly as confirmation of target engagement and longitudinally to assess progression rates of disease in these PD subtypes.”
BackgroundMa, Y., Song, R., & Duan, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1542369 · Cited by 37 · see citing works
Alpha‐synuclein‐associated changes in PINK1‐PRKN‐mediated mitophagy are disease context dependent
Hou, X., Chen, T. H., Koga, S., Bredenberg, J. M., Faroqi, A. H., Delenclos, M., Bu, G., Wszołek, Z. K., Carr, J. A., Ross, O. A., et al. (2023) · Brain Pathology · doi:10.1111/bpa.13175 · Cited by 42 · see citing works
“Plates were imaged on a BD Pathway 855 (BD Biosciences, San Jose, CA, USA) with a 20 objective using a 2 2 montage (no gaps) with laser autofocus every second frame as previously described [33].”
BackgroundMethodInfluentialSelf-citationThe Long and the Short of PTEN in the Regulation of Mitophagy
Wang, L., Lu, G. X., & Shen, H. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00299 · Cited by 45 · see citing works
“pSer65-Ub levels are very low in healthy mitochondria, but dramatically increased after mitochondrial damage and also increased during aging or in PD patient brain, which highlights its roles in diseases (Fiesel et al., 2015; Hou et al., 2018).”
BackgroundCompromised autophagy and mitophagy in brain ageing and Alzheimer’s diseases.
Caponio, D., Veverová, K., Zhang, S.-Q., Shi, L., Wong, G., Vyhnalek, M., & Fang, E. F. (2022) · Aging Brain · doi:10.1016/j.nbas.2022.100056 · Cited by 45 · see citing works
“p-S65-Ub is barely detectable in basal conditions but rapidly increases upon mitochondrial damage [37].”
BackgroundThe Dawn of Mitophagy: What Do We Know by Now?
Belousov, D. M., Вячеславовна, М. Е., Somasundaram, S. G., Kirkland, C. E., & Aliev, G. M. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200522202319 · Cited by 59 · see citing works
“PINK1-mediated ubiquitin phosphorylation at S65 is required for the E3ubiquitin ligase activity of Parkin facilitation [12, 138, 139].”
BackgroundPINK1-Parkin signaling in Parkinson’s disease: Lessons from Drosophila
Imai, Y. (2020) · Neuroscience Research · doi:10.1016/j.neures.2020.01.016 · Cited by 41 · see citing works
Early-Onset Parkinson’s Disease: Creating the Right Environment for a Genetic Disorder
Kolicheski, A., Turcano, P., Tamvaka, N., McLean, P. J., Springer, W., Savica, R., & Ross, O. A. (2022) · Journal of Parkinson s Disease · doi:10.3233/jpd-223380 · Cited by 51 · see citing works
Self-citationWu, Z., Berlemann, L. A., Bader, V., Sehr, D. A., Dawin, E., Covallero, A., Meschede, J., Angersbach, L., Showkat, C., Michaelis, J. B., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2022112006 · Cited by 40 · see citing works
Self-citationNrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease
Marchetti, B. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101664 · Cited by 49 · see citing works
PTEN ‐induced kinase 1 is associated with renal aging, via the cGAS ‐ STING pathway
Ha, M. H., Kim, M. S., An, H., Sung, M. J., Lee, Y. H., Yang, D. H., Jung, S. H., Baek, J., Choi, Y., Taylor, D. M., et al. (2023) · Aging Cell · doi:10.1111/acel.13865 · Cited by 42 · see citing works
“Fiesel et al. (2015) showed that ubiquitin phosphorylation is promoted by PINK1 and accumulates in the elderly population and Pickrell et al. (2015) reported this phenomenon in mice.”
BackgroundMarotta, N., Kim, S., & Krainc, D. (2020) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2020.1703671 · Cited by 39 · see citing works
“Previous studies on PD iNs have shown that PINK1 Q456X iNs do not demonstrate pS65-ubiquitin accumulation upon mitochondrial damage [181] and that bothp.”
BackgroundpiR-823 inhibits cell apoptosis via modulating mitophagy by binding to PINK1 in colorectal cancer
Wang, S., Jiang, X.-Y., Xie, X.-L., Yin, J., Zhang, J.-N., Liu, T., Chen, S.-J., Wang, Y.-J., Zhou, X., Wang, Y.-J., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04922-6 · Cited by 36
Generation of phospho‐ubiquitin variants by orthogonal translation reveals codon skipping
George, S., Aguirre, J., Spratt, D., Bi, Y.-M., Jeffery, M., Shaw, G. S., & O'Donoghue, P. (2016) · FEBS Letters · doi:10.1002/1873-3468.12182 · Cited by 35 · see citing works
Ubiquitination at the mitochondria in neuronal health and disease
Covill‐Cooke, C., Howden, J. H., Birsa, N., & Kittler, J. T. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.07.003 · Cited by 31 · see citing works
Han, R., Wang, Q., Xiong, X., Chen, X.-S., Tu, Z.-C., Li, B., Zhang, F., Chen, C.-Y., Pan, M., Xu, T., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci179633 · Cited by 31 · see citing works
Self-citationCommon Principles and Specific Mechanisms of Mitophagy from Yeast to Humans
Kumar, R., & Reichert, A. S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094363 · Cited by 33 · see citing works
“Thus, phosphorylated ubiquitin pSer65-Ub is reversible and barely detectable in basal conditions, but rapidly induced by mitochondrial damage in cells and amplified by functional PARKIN [74].”
BackgroundPPEF2 Opposes PINK1-Mediated Mitochondrial Quality Control by Dephosphorylating Ubiquitin
Wall, C. E., Rose, C. M., Adrian, M., Zeng, Y. J., Kirkpatrick, D. S., & Bingol, B. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.130 · Cited by 41 · see citing works
Structure-based design and characterization of Parkin-activating mutations
Stevens, M., Croteau, N., Eldeeb, M. A., Antico, O., Zeng, Z. W., Toth, R. L., Durcan, T. M., Springer, W., Fon, E. A., Muqit, M. M. K., et al. (2023) · Life Science Alliance · doi:10.26508/lsa.202201419 · Cited by 32 · see citing works
“Furthermore, pUb, which can be detected in human and rodent brains (Fiesel et al, 2015), is absent in PINK1-null mammals and reduced in Parkin-null or Parkin S65A mutant knock-in mice, and is increased in the mutator mouse and sporadic PD patients (Pickrell et al, 2015; McWilliams et al, 2018a; Hou…”
Self-citationThe application of in vitro ‐derived human neurons in neurodegenerative disease modeling
D’Souza, G. X., Rose, S. E., Knupp, A., Nicholson, D. A., Keene, C. D., & Young, J. E. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24615 · Cited by 35 · see citing works
“…and the retention of dopaminergic properties of the iNs (Liu et al., 2012). iN models have also been used to investigate ubiquitin phosphorylation in PD (Fiesel et al., 2015) and to assess the PTEN-induced putative kinase 1 (PINK1) p.G411S mutation as a risk factor for PD (Puschmann et al., 2017).”
MethodSubstitution of PINK1 Gly411 modulates substrate receptivity and turnover
Fiesel, F. C., Fričová, D., Hayes, C. S., Coban, M. A., Hudec, R., Bredenberg, J. M., Broadway, B. J., Markham, B. N., Yan, T., Boneski, P. K., et al. (2023) · Autophagy · doi:10.1080/15548627.2022.2151294 · Cited by 29 · see citing works
Self-citationBasal activity of PINK1 and PRKN in cell models and rodent brain
Watzlawik, J., Fiesel, F. C., Fiorino, G., Bustillos, B. A., Baninameh, Z., Markham, B. N., Hou, X., Hayes, C. S., Bredenberg, J. M., Kurchaba, N. W., et al. (2023) · Autophagy · doi:10.1080/15548627.2023.2286414 · Cited by 28 · see citing works
“With mitochondrial stress, PRKN levels remained unchanged in cells with two mutant alleles [17], but after 2 h of valinomycin, levels of PRKN decreased in the WT cells.”
BackgroundSelf-citationPINK1-Dependent Mitophagy Inhibits Elevated Ubiquitin Phosphorylation Caused by Mitochondrial Damage
Lambourne, O. A., Bell, S., Wilhelm, L. P., Yarbrough, E. B., Holly, G., Russell, O., Alghamdi, A. M., Fdel, A. M., Varricchio, C., Lane, E., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00555 · Cited by 28 · see citing works
Imaging Findings and Toxicological Mechanisms of Nervous System Injury Caused by Diquat
Ren, Y., Guo, F., & Wang, L. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04172-x · Cited by 25 · see citing works
Methamphetamine-induced dopaminergic neurotoxicity as a model of Parkinson’s disease
Shin, E., Jeong, J. H., Hwang, Y., Sharma, N., Dang, D., Nguyen, B.-T., Nah, S.-Y., Jang, C., Bing, G., Nabeshima, T., et al. (2021) · Archives of Pharmacal Research · doi:10.1007/s12272-021-01341-7 · Cited by 31 · see citing works
Crosstalk between Autophagy and Nanomaterials: Internalization, Activation, Termination
Wei, F., & Duan, Y. (2018) · Advanced Biosystems · doi:10.1002/adbi.201800259 · Cited by 29 · see citing works
Defects of Nutrient Signaling and Autophagy in Neurodegeneration
Ondaro, J., Hernández-Eguiazu, H., Garciandia-Arcelus, M., Loera‐Valencia, R., Rodríguez-Gómez, L., Jiménez-Zúñiga, A., Goikolea, J., Rodriguez‐Rodriguez, P., Ruiz‐Martínez, J., Moreno, F., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.836196 · Cited by 27 · see citing works
“Phosphorylated ubiquitin, as mitophagy tag, is increased in PD patients and correlates with tau tangles and levels of Lewy Bodies (LB) (Fiesel et al., 2015; Hou et al., 2018).”
BackgroundKato, Y., & Sakamoto, K. (2021) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2021.06.015 · Cited by 24
Attacking COVID-19 Progression Using Multi-Drug Therapy for Synergetic Target Engagement
Coban, M., Morrison, J., Maharjan, S., Medina, D. H. H., Li, W.-L., Zhang, Y. S., Freeman, W., Radisky, E. S., Roch, K. L. L., Weisend, C. M., et al. (2020) · Biomolecules · doi:10.3390/biom11060787 · Cited by 24 · see citing works
“ed (Abdul-Hay et al., 2013; Ando et al., 2017; Caulfield and Devkota, 2012; Caulfield and Medina-Franco, 2011; Caulfield, 2011; Caulfield et al., 2011; Caulfield et al., 2014; Caulfield et al., 2015; Fiesel et al., 2015a; Fiesel et al., 2015b; Puschmann et al., 2017; Zhang et al., 2013). Local residues within the 12Å…”
MethodSelf-citationAutophagy in adult stem cell homeostasis, aging, and disease therapy
Zhao, K., Chan, I. T. C., Tse, E. H. Y., Xie, Z., Cheung, T. H., & Zeng, Y. A. (2025) · Cell Regeneration · doi:10.1186/s13619-025-00224-2 · Cited by 22 · see citing works
“…(Nix/BNIP3L), BCL2/adenovirus E1B interacting protein 3 (BNIP3), and FUN14 domain containing 1 (FUNDC1) all contain the LC3-interacting region (LIR) which selectively target damaged mitochondria for degradation without ubiquitination (Fiesel et al. 2015; Shiba-Fukushima et al. 2017; Chu 2019).”
Role of GBA variants in Lewy body disease neuropathology
Walton, R. L., Koga, S., Beasley, A., White, L. J., Griesacker, T., Murray, M., Kasanuki, K., Hou, X., Fiesel, F. C., Springer, W., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02699-w · Cited by 23 · see citing works
Self-citationOrganelle aging: Lessons from model organisms
Bouska, M. J., Huang, K., Kang, P., & Bai, H. (2019) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2019.03.011 · Cited by 27 · see citing works
“Mitophagy is known to be regulated by a group of evolutionarily conserved factors (Fiesel et al., 2015), such as PINK1 (PTEN-induced putative kinase 1) and Parkin (an E3 ubiquitin ligase).”
BackgroundLu, J., Florio, D. N. D., Boya, P., Maday, S., Springer, W., & Chu, C. T. (2025) · Autophagy · doi:10.1080/15548627.2025.2581217 · Cited by 21 · see citing works
“The levels of p-S65-Ub increase during the normal aging process, and are higher in patient brains affected by AD [492], Dementia with Lewy Bodies [493] and PD [360], but not multiple system atrophy [494].”
Self-citationInterplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG
Ligezka, A., Budhraja, R., Nishiyama, Y., Fiesel, F. C., Preston, G., Edmondson, A., Ranatunga, W. K., Hove, J. V. V., Watzlawik, J., Springer, W., et al. (2023) · Genes · doi:10.3390/genes14081585 · Cited by 20 · see citing works
“W used a previously established sensitive ELISA assay as a r adout for phosphor– ubiquitin (p-S65-Ub) th t is PINK1-and PRKN-dependently generated upon mitochondrial damage and serves as a specific marker for mitophagy induction [34,40,41].”
BackgroundMethodSelf-citationLammers, A., Goedhart, M. J., & Avraamidou, L. (2019) · International Journal of Science Education · doi:10.1080/09500693.2019.1675197 · Cited by 21 · see citing works
“After the reading tasks (at the end of the first week) students wrote a brief literature review (750–1000 words) in English in which two articles (A: Koyano et al., 2014; B: Fiesel et al., 2015) are compared, evaluated, and synthesised to answer a central question (see thewriting task inAppendix 1).”
BackgroundCaulfield, T., Richter, J. E., Brown, E., Mohammad, A. N., Judge, D., & Atwal, P. (2018) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.401 · Cited by 19
“…methods (Abdul-Hay et al., 2013; Ando et al., 2017; Caulfield, 2011; Caulfield & Devkota, 2012; Caulfield, Fiesel, & Springer, 2015; Caulfield & Medina-Franco, 2011; Caulfield et al., 2011, 2014; Fiesel et al., 2015, 2015; LopezVallejo et al., 2011; Puschmann et al., 2017; Zhang et al., 2013).”
Self-citation
- 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
- Published
- 2015-07-14
- Volume
- 16
- Issue
- 9
- Pages
- 1114-1130
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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