The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
(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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
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
Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65
Kazlauskaite, A., Kondapalli, C., Gourlay, R., Campbell, D. G., Ritorto, M. S., Hofmann, K., Alessi, D. R., Knebel, A., Trost, M., & Muqit, M. M. K. (2014) · Biochemical Journal · doi:10.1042/bj20140334 · Cited by 806
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 · cited 1×
“PINK1 has been shown to phosphorylate Parkin [4–6] in its N-terminal Ub-like (UBL) domain, which is required for Parkin’s structural [7] and functional activation [8].”
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
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
Flagged first, then by citations
Research works printed but not linked: 37
- Scarffe LA, Stevens DA, Dawson VL, Dawson TM (2014) Parkin and PINK1: much more than mitophagy. Trends Neurosci 37: 315–324 · 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 (2012) PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol 2: 120080 · DOI · Paper page
- Caulfield TR, Fiesel FC, Moussaud‐Lamodiere EL, Dourado DF, Flores SC, Springer W (2014) Phosphorylation by PINK1 releases the UBL domain and initializes the conformational opening of the E3 ubiquitin ligase Parkin. PLoS Comput Biol 10: e1003935 · DOI
- Shiba‐Fukushima K, Inoshita T, Hattori N, Imai Y (2014b) PINK1‐mediated phosphorylation of Parkin boosts Parkin activity in Drosophila. PLoS Genet 10: e1004391 · DOI
- Fiesel FC, Moussaud‐Lamodiere EL, Ando M, Springer W (2014) A specific subset of E2 ubiquitin‐conjugating enzymes regulate Parkin activation and mitophagy differently. J Cell Sci 127: 3488–3504
- Kazlauskaite A, Kelly V, Johnson C, Baillie C, Hastie CJ, Peggie M, Macartney T, Woodroof HI, Alessi DR, Pedrioli PG et al (2014a) Phosphorylation of Parkin at Serine65 is essential for activation: elaboration of a Miro1 substrate‐based assay of Parkin E3 ligase activity. Open Biol 4: 130213 · DOI
- Dikic I, Bremm A (2014) DUBs counteract parkin for efficient mitophagy. EMBO J 33: 2442–2443 · DOI
- Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ (2014) PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 205: 143–153 · 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 (2014) Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510: 162–166 · 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 (2014) Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell 56: 360–375 · DOI
- Shiba‐Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N, Imai Y (2014a) Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet 10: e1004861 · DOI
- Zhang C, Lee S, Peng Y, Bunker E, Giaime E, Shen J, Zhou Z, Liu X (2014) PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions. Curr Biol 24: 1854–1865 · DOI
- Wauer T, Swatek KN, Wagstaff JL, Gladkova C, Pruneda JN, Michel MA, Gersch M, Johnson CM, Freund SM, Komander D (2014) Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis. EMBO J 34: 307–325 · DOI
- Okatsu K, Koyano F, Kimura M, Kosako H, Saeki Y, Tanaka K, Matsuda N (2015) Phosphorylated ubiquitin chain is the genuine Parkin receptor. J Cell Biol 209: 111–128 · 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 (2014) Early‐onset Parkinson's disease due to PINK1 p. Q456X mutation–clinical and functional study. Parkinsonism Relat Disord 20: 1274–1278 · DOI
- Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang WY, Fostvedt E, Jansen‐West K, Belzil VV, Desaro P et al (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)‐associated defects in c9FTD/ALS. Neuron 83: 1043–1050 · 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 (2010) PINK1‐linked parkinsonism is associated with Lewy body pathology. Brain 133: 1128–1142 · DOI
- Riley BE, Olzmann JA (2015) A polyubiquitin chain reaction: parkin recruitment to damaged mitochondria. PLoS Genet 11: e1004952 · DOI
- Lu W, Karuppagounder SS, Springer DA, Allen MD, Zheng L, Chao B, Zhang Y, Dawson VL, Dawson TM, Lenardo M (2014) Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson's‐like movement disorder. Nat Commun 5: 4930 · DOI
- Imai Y, Kanao T, Sawada T, Kobayashi Y, Moriwaki Y, Ishida Y, Takeda K, Ichijo H, Lu B, Takahashi R (2010) The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila. PLoS Genet 6: e1001229 · DOI
- Palikaras K, Tavernarakis N (2012) Mitophagy in neurodegeneration and aging. Front Genet 3: 297 · DOI
- Zhang YJ, Caulfield T, Xu YF, Gendron TF, Hubbard J, Stetler C, Sasaguri H, Whitelaw EC, Cai S, Lee WC et al (2013) The dual functions of the extreme N‐terminus of TDP‐43 in regulating its biological activity and inclusion formation. Hum Mol Genet 22: 3112–3122 · DOI
- Cai Q, Zakaria HM, Simone A, Sheng ZH (2012) Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons. Curr Biol 22: 545–552 · DOI
- Lin WL, Castanedes‐Casey M, Dickson DW (2009) Transactivation response DNA‐binding protein 43 microvasculopathy in frontotemporal degeneration and familial Lewy body disease. J Neuropathol Exp Neurol 68: 1167–1176 · DOI
- Weeks SD, Grasty KC, Hernandez‐Cuebas L, Loll PJ (2009) Crystal structures of Lys‐63‐linked tri‐ and di‐ubiquitin reveal a highly extended chain architecture. Proteins 77: 753–759 · DOI
- Zhang N, Wang Q, Ehlinger A, Randles L, Lary JW, Kang Y, Haririnia A, Storaska AJ, Cole JL, Fushman D et al (2009) Structure of the s5a:k48‐linked diubiquitin complex and its interactions with rpn13. Mol Cell 35: 280–290 · DOI
- Jacobson MP, Friesner RA, Xiang Z, Honig B (2002) On the role of the crystal environment in determining protein side‐chain conformations. J Mol Biol 320: 597–608 · DOI
- Krieger E, Joo K, Lee J, Raman S, Thompson J, Tyka M, Baker D, Karplus K (2009) Improving physical realism, stereochemistry, and side‐chain accuracy in homology modeling: four approaches that performed well in CASP8. Proteins 77(Suppl 9): 114–122 · DOI
- Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst 26: 283–291 · DOI · Paper page
- Joosten RP, Salzemann J, Bloch V, Stockinger H, Berglund AC, Blanchet C, Bongcam‐Rudloff E, Combet C, Da Costa AL, Deleage G et al (2009) PDB_REDO: automated re‐refinement of X‐ray structure models in the PDB. J Appl Crystallogr 42: 376–384 · DOI
- Krieger E, Nabuurs SB, Vriend G (2003) Homology modeling. Methods Biochem Anal 44: 509–523 · DOI
- Vriend G (1990) WHAT IF: a molecular modeling and drug design program. J Mol Graph 8: 52–56, 29 · DOI
- Caulfield TR, Devkota B, Rollins GC (2011) Examinations of tRNA Range of Motion Using Simulations of Cryo‐EM Microscopy and X‐Ray Data. J Biophys 2011: 219515
- Krieger E, Dunbrack RL Jr, Hooft RW, Krieger B (2012) Assignment of protonation states in proteins and ligands: combining pKa prediction with hydrogen bonding network optimization. Methods Mol Biol 819: 405–421 · DOI
- Schrödinger (2010) Maestro, version 9.1. New York, NY: Schrödinger, LLC
- Schrödinger (2012) Suite 2012. New York, NY: Schrödinger, LLC
- Schrödinger (2013) Biologics Suite: BioLuminate, version 1.1. New York, NY: Schrödinger, LLC
Cited by
Sorted by citations
Items 101–167 of 167
DDIT3/CHOP promotes LPS/ATP-induced pyroptosis in osteoblasts via mitophagy inhibition
Dong, Z., Yang, B., Jia, M., Yang, C., Wang, S., Mu, H., & Wang, J. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2024.119712 · Cited by 15
Gao, H., Jensen, K. N., Nesbitt, J. J., Ostroot, M., Cary, G. A., Wiley, J. C., Trushin, S., Watzlawik, J. O., Springer, W., Galkin, A. S., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70519 · Cited by 22
“48,49,53 Previously, prominent accumulation of p-S65-Ub was demonstrated in autopsied brains of patients with AD.”
Self-citationJiao, F., Meng, L., Du, K., & Li, X. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01195 · Cited by 30
“It was found that pSer65Ub formation increased in the postmortem PD brain and decreased in patients with PINK1/parkin mutation, suggesting the relevance of the PINK1/parkin-mediated mitophagy in PD (Fiesel et al., 2015; Hou et al., 2018).”
BackgroundTemporal integration of mitochondrial stress signals by the PINK1:Parkin pathway
Bowling, J. L., Skolfield, M. C., Riley, W. A., Nolin, A. P., Wolf, L. C., & Nelson, D. E. (2019) · BMC Molecular and Cell Biology · doi:10.1186/s12860-019-0220-5 · Cited by 21
“This has been tested in vitro in various studies using reversible inhibitors of oxidative phosphorylation, such as carbonyl cyanide m– chlorophenyl hydrazone (CCCP), applied at high concentrations to completely depolarize the mitochondria for different periods of time [25, 26].”
MethodPost-translational modification and mitochondrial function in Parkinson’s disease
Luo, S., Wang, D., & Zhang, Z. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1329554 · Cited by 14
Mitochondrial biogenesis in organismal senescence and neurodegeneration
Daskalaki, I., & Tavernarakis, N. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111345 · Cited by 18
Stress-induced phospho-ubiquitin formation causes parkin degradation
Kovalchuke, L., Mosharov, E. V., Levy, O. A., & Greene, L. A. (2019) · Scientific Reports · doi:10.1038/s41598-019-47952-5 · Cited by 15
“In accordance with this process, parkin activity has been found to increase the total amount of cellular phospho-Ub following mitochondrial depolarization [69].”
BackgroundInfluentialNLRP3 Inflammasome Activation and Altered Mitophagy Are Key Pathways in Inclusion Body Myositis
Naddaf, E., Nguyen, T. K. O., Watzlawik, J. O., Gao, H., Hou, X., Fiesel, F. C., Mandrekar, J. N., Kokesh, E., Harmsen, W. S., Lanza, I. R., et al. (2024) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13672 · Cited by 17
“The p- S65-Ub antibody was developed in house and fully characterized and validated in cells and human tissue [23, 24].”
Self-citationThe Ubiquitin Proteasome System as a Therapeutic Area in Parkinson’s Disease
Kumar, S., Mattern, M. R., Goldberg, M. S., & Butt, T. R. (2023) · NeuroMolecular Medicine · doi:10.1007/s12017-023-08738-1 · Cited by 16
“Phospho-Ub is considered a potential biomarker in Parkinson’s disease (Fiesel et al., 2015).”
Watzlawik, J. O., Hou, X., Richardson, T., Lewicki, S. L., Siuda, J. S., Wszołek, Z. K., Cook, C. N., Petrucelli, L., Deture, M. A., Dickson, D. W., et al. (2024) · Autophagy · doi:10.1080/15548627.2024.2356490 · Cited by 14
Self-citationTufi, R., Clark, E., Hoshikawa, T., Tsagkaraki, C., Stanley, J., Takeda, K., Staddon, J., & Briston, T. (2022) · bioRxiv · doi:10.1101/2022.09.30.509127 · Cited by 12
Alterations of PINK1-PRKN signaling in mice during normal aging
Baninameh, Z., Watzlawik, J. O., Hou, X., Richardson, T., Kurchaba, N. W., Yan, T., Florio, D. N. D., Fairweather, D., Kang, L., Nguyen, J. H., et al. (2024) · Autophagy Reports · doi:10.1080/27694127.2024.2434379 · Cited by 12
“Following blocking with 5% normal goat serum (Invitrogen, 16210-072) for 20 minutes, sections were incubated with primary antibody against pS65-Ub (in-house, 1:250) [17] that was diluted in Dako Antibody Diluent with Background Reducing Components (Agilent, S3022) for 45 minutes at room temperature.”
Self-citationHines, S. L., Richter, J. E., Mohammad, A. N., Mahim, J., Atwal, P., & Caulfield, T. (2019) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.566 · Cited by 10
Self-citationMitochondrial quality control in health and disease: mechanisms and therapeutic targets
Creus, A., Mohapatra, S., Ortega, L., & Sebastián, D. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02813-2 · Cited by 7
“436 437 – 439 Other aspects related to MQC and their role in aging Genomic instability affecting mtDNA has been proposed to contribute to aging and age-related pathologies.”
Mitochondrial quality control in human ageing and longevity
Picca, A., & Ferrucci, L. (2026) · Nature Metabolism · doi:10.1038/s42255-026-01563-3 · Cited by 10
“These alterations suggest that mitophagy is disrupted at both its initiation and degradation stages 87–89 .”
Dafsari, H. S., Deneubourg, C., Singh, K., Maroofian, R., Suprenant, Z., Kho, A. L., Ingham, N. J., Steel, K. P., Sheshadri, P., Baur, F., et al. (2025) · Annals of Neurology · doi:10.1002/ana.78013 · Cited by 10
“32 Histochemical analysis of substantia nigra sections from PARK2 - and PINK1 -mutated patients also feature pS65-Ub punctae colocalizing with mitochondria and lysosomes similar our observations in EPG5 -mutated cells.”
Self-citationGenome‐wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease
Hou, X., Heckman, M. G., Fiesel, F. C., Koga, S., Soto‐Beasley, A. I., Watzlawik, J. O., Zhao, J., Valentino, R. R., Johnson, P. W., White, L. J., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70198 · Cited by 9
Self-citationParkinson’s Disease: Are PINK1 Activators Inching Closer to the Clinic?
Mehellou, Y. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.3c00070 · Cited by 13
Tang, C., & Zhang, W. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b00715 · Cited by 15
Monogenetic Forms of Parkinson’s Disease – Bridging the Gap Between Genetics and Biomarkers
Tönges, L., Kwon, E. H., & Klebe, S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.822949 · Cited by 9
Hines, S. L., Mohammad, A. N., Jackson, J., Macklin, S., & Caulfield, T. (2019) · Molecular Omics · doi:10.1039/c8mo00137e · Cited by 8
Self-citationFunction and regulation of the mitochondrial stress response
Sheetz, J. B., Chandrasekhar, S., & Rapé, M. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-026-01769-9 · Cited by 8
Chen, C., Gao, T.-Y., Yi, H., Zhang, Y., Wang, T., Lou, Z., Wei, T.-F., Lu, Y.-B., Li, T., Tang, C., et al. (2025) · bioRxiv · doi:10.7554/elife.103945 · Cited by 7
“Beyond specific neurodegenerative diseases, pUb elevation also appears to be associated with the aging process itself [15, 16], a physiological condition often accompanied by gradual neurodegeneration.”
Development and validation of a sensitive sandwich ELISA against human PINK1
Baninameh, Z., Watzlawik, J. O., Bustillos, B. A., Fiorino, G., Yan, T., Lewicki, S. L., Zhang, H., Dickson, D. W., Siuda, J. S., Wszołek, Z. K., et al. (2025) · Autophagy · doi:10.1080/15548627.2025.2457915 · Cited by 9
“We have previously developed p-S65-Ub antibodies that can be used for immunohistochemistry and have established a sensitive p-S65-Ub ELISA as a surrogate for PINK1-PRKN mitophagy [28,29].”
Self-citationMethods to detect mitophagy in neurons during disease
Carter, F. E., Moore, M. E., & Pickrell, A. M. (2019) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2019.108351 · Cited by 8
“However, antibody detection of phosphorylated Ser65 UB found an accumulation of signal in the soma of aged healthy and PD human postmortem dopaminergic (DA) neurons (Fiesel et al., 2015).”
BackgroundTRIO gene segregation in a family with cerebellar ataxia.
Al-Shaikh, R. H., Caulfield, T., Strongosky, A., Matthew, M., Jansen-West, K. R., Prudencio, M., Fryer, J., Petrucelli, L., Uitti, R., & Wszolek, Z. (2018) · Neurologia i Neurochirurgia Polska · doi:10.1016/j.pjnns.2018.09.006 · Cited by 7
“[32] Fiesel FC, Ando M, Hudec R, Hill AR, Castanedes-Casey M, Caulfield TR, et al.”
BackgroundSelf-citationHarris, A. L., Blackburn, P., Richter, J. E., Gass, J., Caulfield, T., Mohammad, A. N., & Atwal, P. (2018) · Case Reports in Genetics · doi:10.1155/2018/6968395 · Cited by 7
Self-citationMatsuda, N., & Tanaka, K. (2015) · Nature · doi:10.1038/nature15199 · Cited by 6
Disease Modeling of Neurodegenerative Disorders Using Direct Neural Reprogramming
Legault, E. M., Bouquety, J., & Drouin‐Ouellet, J. (2022) · Cellular Reprogramming · doi:10.1089/cell.2021.0172 · Cited by 7
“Together, these studies showed that the deficits in the PINK1/Parkin pathway could be modeled in iNs, although these features were also observed in parental fibroblasts, except for differences in neurite length seen in Pu et al. (2020).”
InfluentialRichter, J. E., Hines, S., Selvam, P., Atwal, H. K., Farres, H., Caulfield, T., & Atwal, P. (2021) · Cancer Genetics · doi:10.1016/j.cancergen.2021.01.004 · Cited by 6
Self-citationQu, Y., Ren, S.-H., Liao, Y., Qiu, X., Tan, L., Song, C.-P., Sun, Y.-J., & Ding, C. (2026) · Autophagy · doi:10.1080/15548627.2026.2624746 · Cited by 5
“Consequently, phosphorylated ubiquitin (p-S65-Ub) has been identified as a biomarker for detecting the activation of PINK1-PRKN-mediated mitophagy [46].”
Hippocampal mitophagy alterations in MAPT-associated frontotemporal dementia with parkinsonism
Richardson, T., Hou, X., Fiesel, F. C., Wszolek, Z., Dickson, D. W., & Springer, W. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-01955-8 · Cited by 5
“Together they selectively decorate damaged mitochondria with phos-pho-serine 65 ubiquitin (pS65-Ub) [19, 54].”
InfluentialSelf-citationMoving CNS axon growth and regeneration research into human model systems
Lear, B. P., & Moore, D. L. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1198041 · Cited by 5
“In recent years, in vitro directly reprogrammed neurons have become a powerful tool to study the molecular underpinnings of aging in neurons, and to model neurodegenerative diseases (Liu et al., 2014; Fiesel et al., 2015; Lim S. M. et al., 2016; Liu M. L. et al., 2016; Victor et al., 2018; Mertens et al., 2021; Vasan…”
BackgroundQin, L., Gong, Z., Liu, K., Dong, X., & Tang, C. (2021) · Biomolecules · doi:10.3390/biom11071008 · Cited by 5
“An increase of S65-phosphorylated Ub (pUb) level has been observed in neurons and brains of the aging population and neurodegenerative disease patients [18,19].”
BackgroundRichter, J. E., Samreen, A., Vadlamudi, C., Helmi, H., Mohammad, A. N., Wierenga, K., Hines, S. L., Atwal, P., & Caulfield, T. (2019) · Medicina · doi:10.3390/medicina55050137 · Cited by 5
Self-citationNon-radioactive in vitro PINK1 Kinase Assays Using Ubiquitin or Parkin as Substrate
Fiesel, F. C., Hudec, R., & Springer, W. (2016) · Bio-protocol · doi:10.21769/bioprotoc.1946 · Cited by 5
Self-citationAlterations of PINK1-PRKN signaling in mice during normal agingPreprint
Baninameh, Z., Watzlawik, J., Hou, X., Richardson, T., Kurchaba, N. W., Yan, T.-X., Florio, D. N. D., Fairweather, D., Kang, L., Nguyen, J. H., et al. (2024) · bioRxiv · doi:10.1101/2024.04.29.591753 · Cited by 4
“Following blocking with 5% normal goat serum (Invitrogen, 16210-072) for 20 minutes, sections were incubated with primary antibody against pS65-Ub (in-house, 1:250) [20] that was diluted in Dako Antibody Diluent with Background Reducing Components (Agilent, S3022) for 45 minutes at room temperature.”
InfluentialSelf-citationMacklin, S., Bruno, K. A., Vadlamudi, C., Helmi, H., Samreen, A., Mohammad, A. N., Hines, S. L., Atwal, P., & Caulfield, T. (2020) · Case Reports in Medicine · doi:10.1155/2020/5108052 · Cited by 4
Self-citationThe role of phospho-ubiquitin in mitochondrial health and diseases
Suresh, K., Rainville, C., Sterner, D. E., Goldberg, M. S., & Butt, T. R. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113128 · Cited by 3
“In 2015, Fiesel et al. reported generation of rabbit polyclonal antibodies against pUb (73).”
InfluentialAssociation of mitochondrial genetic background with pS65-Ub in Lewy body disease
Tran, N. L. K., Hou, X., Heckman, M., Fiesel, F. C., Koga, S., Watkins, M. M., Sledge, H. J., Gibbs, J., Traynor, B., Dalgard, C. L., et al. (2026) · Acta Neuropathologica · doi:10.1007/s00401-026-02993-9 · Cited by 3
Self-citationTargeting of kinases to treat neurodegenerative diseases
Shomali, T., & Trempe, J.-F. (2026) · Pharmacological Reviews · doi:10.1016/j.pharmr.2026.100128 · Cited by 4
“28 However, unlike LRRK2, no selective PINK1 agonist has yet entered clinical trials, largely because of the absence of potent, selective small-molecule activators and challenges associated with stabilizing the kinase in its active conformation.”
Hou, X., Heckman, M. G., Fiesel, F. C., Koga, S., Soto‐Beasley, A. I., Watzlawik, J. O., Zhao, J., Valentino, R. R., Johnson, P. W., White, L. J., et al. (2023) · medRxiv · doi:10.1101/2023.10.16.23297100 · Cited by 6
Self-citationSelvam, P., Jain, A., Abbott, J., Ahuja, A., Cheema, A., Bruno, K. A., Atwal, H. K., Forghani, I., Caulfield, T., & Atwal, P. (2022) · Molecular Syndromology · doi:10.1159/000519326 · Cited by 3
“…methods, which have been established [Caulfield, 2011; Caulfield and Medina-Franco, 2011; Caulfield et al., 2011, 2014, 2015; Lopez-Vallejo et al., 2011; Caulfield and Devkota, 2012; Abdul-Hay et al., 2013; Zhang et al., 2013; Fiesel et al., 2015a, b; Ando et al., 2017; Puschmann et al., 2017].”
MethodSelf-citationFunctional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics
Dongdem, J. T., & Wezena, C. A. (2021) · Biochemistry · doi:10.5772/intechopen.100534 · Cited by 5
Norris, G., Tsai, A., Schneider, K., Wu, Y., Caulfield, T., & Green, A. (2021) · Cancer Genetics · doi:10.1016/j.cancergen.2021.01.008 · Cited by 3
Self-citationCharacterization of a Pathogenic Variant in the ABCD1 Gene Through Protein Molecular Modeling
Richter, J. E., Vadlamudi, C., Macklin, S., Samreen, A., Helmi, H., Broderick, D. F., Mohammad, A. N., Hines, S. L., van Gerpen, J. A., Atwal, P. S., et al. (2020) · Case Reports in Genetics · doi:10.1155/2020/3256539 · Cited by 3
Self-citationHou, X., Richardson, T., Heckman, M. G., Fiesel, F. C., White, L. J., Koga, S., Ross, O. A., Dickson, D. W., & Springer, W. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02964-6 · Cited by 2
“Although typically transient, pS65-Ub levels markedly increase with normal aging in mice and in human brain [18–20], which may result from increased mitochondrial damage and activation of PINK1–PRKN and/or from impaired degradation and inefficient flux through lysosomes.”
InfluentialSelf-citationWatzlawik, J., Hou, X., Richardson, T., Lewicki, S. L., Siuda, J., Wszolek, Z., Cook, C., Petrucelli, L., DeTure, M., Dickson, D. W., et al. (2024) · bioRxiv · doi:10.1101/2024.01.15.575715 · Cited by 2
“Given that the reference antibody performs poorly in immunohistochemistry [13], the five p-S65-12 Ub recombinant antibodies were compared with a previously validated in-house p-S65-Ub antibody [11,14] ( Fig.”
BackgroundMethodSelf-citationPhosphorylation at Ser65 modulates ubiquitin conformational dynamics
Yovanno, R. A., Yu, A., Wied, T. J., & Lau, A. Y. (2022) · bioRxiv · doi:10.1101/2022.08.09.502833 · Cited by 2
Mann, G., Sulkshane, P., Sadhu, P., Ziv, T., Glickman, M., & Brik, A. (2022) · Molecules · doi:10.3390/molecules27154867 · Cited by 2
“To the best of our knowledge, mitophagy is the only reported cellular process that specifically utilizes pUb, and PINK1 is the only reported kinase that is specific for phosphorylating Ub at serine 65 [7,8].”
BackgroundTargeting Tmprss2, S-protein:Ace2, and 3CLpro for Synergetic Inhibitory EngagementPreprint
Coban, M., Morrison, J., Freeman, W. E., Radisky, E. S., Roch, K. L. L., & Caulfield, T. (2020) · ChemRxiv · doi:10.26434/chemrxiv.12616151.v1 · Cited by 2
Self-citationLei, Y., Liu, L., & Tang, Y. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103287 · Cited by 1
Gavrielatos, M., Heckman, M. G., Soto‐Beasley, A. I., Blumenfeld, S. G., Hou, X., Koga, S., Murray, M. E., Kasanuki, K., Ono, D., Fiesel, F. C., et al. (2025) · Annals of Neurology · doi:10.1002/ana.78075 · Cited by 1
Self-citationP2RX7 drives inflammatory microglia and pathogenic extracellular vesicle secretion in tauopathy
Bodart‐Santos, V., Ravula, A. R., You, Y., Abdullah, M., Ruan, Z., Ellison, J. W., Radhakishun, S., Ray, N. B., Melvin, B. C., Kurti, A., et al. (2026) · Neuron · doi:10.21203/rs.3.rs-6771517/v1 · Cited by 6
Self-citationChen, C., Yi, H.-W., Zhang, Y., Wang, T., Gao, T., Lou, Z.-L., Wei, T.-F., Lu, Y., Li, T., Zhang, W., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.10.552882
PP2A forestalls mitophagy by dephosphorylating Parkin and ubiquitinPreprint
Ye, S.-X., Liu, X., Nie, Z.-F., Meng, L.-S., Dong, X., Li, F., Gong, Z., Yang, W., Zhang, W., & Tang, C. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.12.484070 · Cited by 1
Ahuja, A. S., Selvam, P., Vadlamudi, C., Chopra, H., Richter, J. E., Macklin, S., Samreen, A., Helmi, H., Mohammaad, A. N., Hines, S. L., et al. (2020) · Ophthalmic Genetics · doi:10.1080/13816810.2020.1814344 · Cited by 1
Self-citationImmunohistochemical Characterization of Phosphorylated Ubiquitin in the Mouse HippocampusPreprint
Kataoka, K., Bilkei‐Gorzó, A., Zimmer, A., & Asahi, T. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.20.912238 · Cited by 1
The PINK1 p.I368N Mutation Affects Protein Stability and Kinase Activity with Its Structural Change
Ando, M., Fiesel, F., Hudec, R., Caulfield, T., Ogaki, K., Górka-Skoczylas, P., Koziorowski, D., Friedman, A., Chen, L., Dawson, V., et al. (2018) · Juntendō Igaku/Juntendo igaku · doi:10.14789/jmj.2018.64.jmjjmj17-r10 · Cited by 1
Self-citationmiRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A
Markham, B. N., Ramnarine, C., Kim, S., Grever, W. E., Soto-Beasley, A. I., Heckman, M. G., Ren, Y., Osborne, A. C., Kehili, M., Bhagwate, A. V., et al. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00029-w
“These serve as a specific signal for the engulfment of mitochondria in autophagosomes [12]. pS65-Ub has been shown to accumulate during aging, stress, and disease [13, 14] further supporting a role of PINK1-PRKN-dependent mitophagy for human disease.”
Self-citationThe mechanism of dietary intervention in delaying brain aging and neurodegenerative diseases
Luo, B., Liu, S., Zheng, L., 张柏雯, Chen, B., Shang, T., Zheng, J., Kuang, B., 周艳玲, Sun, Y., et al. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103417
Repurposing Retatrutide for Neuroprotection in Parkinson’s Disease: A Comprehensive Review
Sivakumar, G., K, T., K., N., A., D., S., K., & Helen, E. (2026) · International Journal of Innovative Science and Research Technology · doi:10.38124/ijisrt/26sep1305
Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration
Basak, B., Riley, J. F., Nataraj, N. M., & Holzbaur, E. L. F. (2026) · Journal of Clinical Investigation · doi:10.1172/jci199847 · Cited by 1
Nadeem, R. I., Sayed, R. H., Elbaz, E., Rahman, A. A. S. A., & Saeed, M. (2026) · Progress in Neuro-psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111781
Wu, Z.-X., Berlemann, L. A., Bader, V., Sehr, D. A., Eilers, E., Covallero, A., Meschede, J., Angersbach, L., Showkat, C., Michaelis, J., et al. (2022) · bioRxiv · doi:10.1101/2022.05.27.493704
“33 Mouse monoclonal anti-ubiquitin Santa Cruz Cat# sc-8017, RRID:AB_628423 Rabbit anti-p-S65-ubiquitin (Fiesel et al., 2015) N/A Rabbit monoclonal anti-Hexokinase I Cell Signaling Technology Cat#2024, RRID:AB_2248227 Rabbit polyclonal anti-Bax Cell Signaling Technology Cat#2772, RRID:AB_10695870 Rabbit monoclonal anti…”
BackgroundSelf-citationStructure-based design and characterization of Parkin activating mutations
Stevens, M., Croteau, N., Eldeeb, M. A., Zeng, Z.-W., Toth, R., Durcan, T., Springer, W., Fon, E., Muqit, M., & Trempe, J. (2022) · bioRxiv · doi:10.1101/2022.02.22.481412
“Furthermore, pUb can be detected in human and rodent brains (Fiesel et al 2015), is absent in PINK1-null mammals and reduced in Parkin-null or ParkinS65A mutant knock-in mice, and is increased in the mutator mouse and sporadic PD patients (Hou et al 2018, McWilliams et al 2018a, Pickrell et al…”
BackgroundSelf-citationModification of small ubiquitin‐related modifier 2 (SUMO2) by phosphoubiquitin in HEK293T cells
Dongdem, J. T., Dawson, S. P., & Layfield, R. (2021) · PROTEOMICS · doi:10.1002/pmic.202000234
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
- 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 › 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
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 ›
Are you an author, or do you see a problem with this page? Request a review
