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Parkin Interacts with Ambra1 to Induce Mitophagy
Open accessAbstract
Mutations in the gene encoding Parkin are a major cause of recessive Parkinson's disease. Recent work has shown that Parkin translocates from the cytosol to depolarized mitochondria and induces their autophagic removal (mitophagy). However, the molecular mechanisms underlying Parkin-mediated mitophagy are poorly understood. Here, we investigated whether Parkin interacts with autophagy-regulating proteins. We purified Parkin and associated proteins from HEK293 cells using tandem affinity purification and identified the Parkin interactors using mass spectrometry. We identified the autophagy-promoting protein Ambra1 (activating molecule in Beclin1-regulated autophagy) as a Parkin interactor. Ambra1 activates autophagy in the CNS by stimulating the activity of the class III phosphatidylinositol 3-kinase (PI3K) complex that is essential for the formation of new phagophores. We found Ambra1, like Parkin, to be widely expressed in adult mouse brain, including midbrain dopaminergic neurons. Endogenous Parkin and Ambra1 coimmunoprecipitated from HEK293 cells, SH-SY5Y cells, and adult mouse brain. We found no evidence for ubiquitination of Ambra1 by Parkin. The interaction of endogenous Parkin and Ambra1 strongly increased during prolonged mitochondrial depolarization. Ambra1 was not required for Parkin translocation to depolarized mitochondria but was critically important for subsequent mitochondrial clearance. In particular, Ambra1 was recruited to perinuclear clusters of depolarized mitochondria and activated class III PI3K in their immediate vicinity. These data identify interaction of Parkin with Ambra1 as a key mechanism for induction of the final clearance step of Parkin-mediated mitophagy.
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“Although the role of ATG4A in mitophagy is unclear, AMBRA1 and ATG12 positively regulate mitophagy [56–58].”
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 [56]
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“Because Parkin is an E3 ubiquitin ligase (Shimura et al., 2000), we asked whether Ambra1 might be a substrate for Parkinmediated ubiquitination.”
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Regulation of Parkin E3 ubiquitin ligase activity
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“There are multiple other interactors of Parkin that as yet are not identified as having regulatory effects on Parkin activity, including Klokin1 and Ambra1, both implicated in mitochondrial homeostasis [114, 115].”
BackgroundmiR-103a-3p regulates mitophagy in Parkinson’s disease through Parkin/Ambra1 signaling
Zhou, J., Zhao, Y., Li, Z., Zhu, M., Wang, Z., Li, Y., Xu, T., Feng, D., Zhang, S., Tang, F., et al. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105197 · Cited by 76
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Andres, A. M., Stotland, A., Queliconi, B. B., & Gottlieb, R. A. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.10.003 · Cited by 78
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Regulation of autophagy and mitophagy by nutrient availability and acetylation
Webster, B. R., Scott, I., Traba, J., Han, K., & Sack, M. N. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2014.02.001 · Cited by 75
“However, Parkin can also link mitophagy to the macroautophagy machinery by directly binding to a protein within the the Beclin1/class III phosphatidylinotisol 3-kinase (PI3K) complex [121] to promote autophagosome nucleation.”
Scott, L., Dawson, V. L., & Dawson, T. M. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.04.008 · Cited by 72
“…of roles for Ambra1 including: (1) interaction with parkin during mitochondrial depolarization, whereupon Ambra1 activates class III PI3K (Van Humbeeck et al., 2011); (2) Ambra1 mediated mitochondrial depolarization and subsequent ubiquitination by parkin; (3) induction of parkin-independent…”
BackgroundRahman, F. A., & Quadrilatero, J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03807-9 · Cited by 77
Beclin 1-Vps34 complex architecture: Understanding the nuts and bolts of therapeutic targets
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“Ambra1, an essential protein for neural tube development, is not only required for starvation-induced autophagy (McKnight et al., 2012), but also involved in mitochondrial dynamics and degradation (Strappazzon et al., 2011, 2014; Van Humbeeck et al., 2011).”
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“For instance, PARKIN is further reported to interact with Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1) that activates BECLIN1 complex, endorsing the AP formation nearby (69).”
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Guo, J., & Chiang, W. (2021) · IUBMB Life · doi:10.1002/iub.2585 · Cited by 60
“After mitophagy induction, AMBRA1 translocates to the depolarized mitochondria in a Parkin-dependent manner and contributes to mitochondrial clearance by locally activating class III PI-3 kinase around damaged mitochondria.(47) AMBRA1 also induces mitophagy by direct interaction with LC3 through a canonical LIR domain…”
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“One group contains a ubiquitin-binding domain which binds to ubiquitinated mitochondria [20], such as p62/SQSTM1, NBR1 (Neighbor of BRCA1 gene 1 protein), optineurin (OPTN) [67,68] and AMBRA1 (autophagy and beclin-1 regulator 1) [69,70].”
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Self-citationMitochondrial quality control in neurodegenerative diseases
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“This Parkin–AMBRA1mediated mechanism for the removal of damaged mitochondria may be involved in the disease process of PD and DLB.”
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Tan, S., & Wong, E. S. P. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/9028435 · Cited by 47
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“An interesting report has shown that AMBRA1 is also involved in a selective form of autophagy called mitophagy.(38) The authors demonstrated binding of endogenous Ambra1 to the E3 ligase Parkin in adult mouse brain.”
BackgroundExpression of Ambra1 in mouse brain during physiological and Alzheimer type aging
Sepe, S., Nardacci, R., Fanelli, F., Rosso, P., Bernardi, C., Cecconi, F., Mastroberardino, P. G., Piacentini, M., & Moreno, S. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.07.001 · Cited by 41
“…in the GL and ML. (C) High-power view of Purkinje neurons, d (C) 100 mm. Abbreviations: Ambra1, Beclin 1 regulated-autophagy; GL, granular layer; localization is also consistent with the described interaction between Ambra1 and Parkin, leading to mitophagy induction (Van Humbeeck et al., 2011).”
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Themistokleous, C., Bagnoli, E., Parulekar, R., & Muqit, M. M. K. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168144 · Cited by 51
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Cross Talk of Proteostasis and Mitostasis in Cellular Homeodynamics, Ageing, and Disease
Gumeni, S., & Trougakos, I. P. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/4587691 · Cited by 43
New therapeutics to modulate mitochondrial dynamics and mitophagy in cardiac diseases
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“During prolonged mitochondrial depolarization parkin also interacts with autophagy/beclin-1 regulator 1 protein (AMBRA1), initiating AMBRA1 promoted autophagy of depolarised mitochondria by activation of class III phosphatidylinositol 3-kinase complex [260,261].”
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“For example, Parkin has been further reported to interact with activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1), which activates the BECLIN1 complex, endorsing the AP formation nearby (Van Humbeeck et al. 2011).”
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“However, co-treatment with 3-MA did not reduce the mitochondrial loss, which indicated inhibitory effect of 3-MAonmitophagy in our system but may not match with the above previous reports [24, 25].”
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“AMBRA1 is also known to be a Parkin-binding protein involved in mitophagy [88].”
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Basak, B., & Holzbaur, E. L. F. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169161 · Cited by 44
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“Therefore, mitochondrial translocation and activation of Parkin play an essential role in priming mitochondria, which occurs via the ubiquitination of specific mitochondrial substrates, to induce autophagy by interaction with Ambra 1 (25).”
BackgroundCorrado, M., Mariotti, F. R., Trapani, L., Taraborrelli, L., Nazio, F., Cianfanelli, V., Soriano, M. E., Schrepfer, E., Cecconi, F., Scorrano, L., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201593727 · Cited by 31
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“A component of the autophagic machinery, Ambra1 (activating molecule in Beclin1-regulated autophagy) was also identified to interact with parkin and promotemitochondrial clearance (Van Humbeeck et al., 2011).”
BackgroundLC3-II may mediate ATR-induced mitophagy in dopaminergic neurons through SQSTM1/p62 pathway
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“Ubiquitination recruits autophagy proteins, such as AMBRA1, thereby initiating mitophagy.(28,33,34)”
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Cadete, V. J. J., Vasam, G., Menzies, K. J., & Burelle, Y. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.11.018 · Cited by 36
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“A possible additional mechanistic aspect is indicated by the interaction of Parkin with Ambra 1 (Figure 3) [136].”
BackgroundAF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson's disease
Haskin, J., Szargel, R., Shani, V., Mekies, L. N., Rott, R., Lim, G. G. Y., Lim, K., Bandopadhyay, R., Wolosker, H., & Engelender, S. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt058 · Cited by 29
“For instance, Ambra1 affects the mitochondrial clearance but not the translocation of parkin (52).”
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BackgroundFrom Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders
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“In contrast, the UPS, which targets proteins for degradation through proteasomes, is essential for the regulation of various cellular processes, including the removal of misfolded proteins and the regulation of signaling pathways critical for neuronal function and survival [276].”
BackgroundMitophagy impairment in neurodegenerative diseases: Pathogenesis and therapeutic interventions
Mani, S., Swargiary, G., & Chadha, R. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.01.001 · Cited by 33
Mitophagy: A New Player in Stem Cell Biology
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“In addition to this role in receptor-dependent mitophagy, AMBRA1 can also promote adaptor-mediated PINK1/Parkin-dependent mitophagy [28,30].”
BackgroundParkin ubiquitinates mTOR to regulate mTORC1 activity under mitochondrial stress
Park, D., Lee, M. N., Jeong, H., Koh, A., Yang, Y. R., Suh, P.-G., & Ryu, S. H. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.06.010 · Cited by 25
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“87 Moreover, Parkin is able to interact with autophagy and beclin 1 regulator 1 (AMBRA1), another driver of autophagy, 88 and is also involved in a non-canonical mechanism of mitochondrial quality assurance, in which vesicles budding off the oxidatively stressed mitochondria are ultimately directed…”
BackgroundThe Role of Mitophagy in Glaucomatous Neurodegeneration
Stavropoulos, D., Grewal, M. K., Petriti, B., Chau, K., Hammond, C. J., Garway‐Heath, D. F., & Lascaratos, G. (2023) · Cells · doi:10.3390/cells12151969 · Cited by 27
AMBRA1 and its role as a target for anticancer therapy
Li, X., Lyu, Y., Li, J., & Wang, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.946086 · Cited by 23
“revealed that AMBRA1 is a non-substrate interactor of E3 ubiquitin ligase Parkin, and the interaction of AMBRA1 and Parkin is enhanced upon mitochondrial depolarization, leading to the clearance of mitochondria in a Parkin-mediated manner (19).”
BackgroundRandhawa, R., Sehgal, M., Singh, T. R., Duseja, A. K., & Changotra, H. (2015) · Gene · doi:10.1016/j.gene.2015.02.056 · Cited by 25
Wang, X., Ma, C., Mi, K., Cao, X., Tan, Y., Yuan, H., Ren, J. T., & Liang, X. (2024) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2024.111363 · Cited by 20
Su, X., Song, C., He, Z., Song, Q., Meng, L., Dong, C., Zhou, J., Hu, K., Xiong, Y., Liu, J., et al. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2023.119604 · Cited by 20
Critical role of dysfunctional mitochondria and defective mitophagy in autism spectrum disorders
Wang, Y., Qiu, M.-Y., Liu, Q., Tang, H., & Gu, H. (2021) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.12.022 · Cited by 30
Regulation of mitochondrial cargo-selective autophagy by posttranslational modifications
Lechado‐Terradas, A., Zittlau, K. I., Maček, B., Fraiberg, M., Elazar, Z., & Kahle, P. J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101339 · Cited by 27
“The activating molecule in beclin-1 regulated autophagy protein 1 (AMBRA1) was identified as a parkin-interacting protein mediating the propagation of mitophagy (129).”
BackgroundValidity of the MPTP-Treated Mouse as a Model for Parkinson’s Disease
Klemann, C. J. H. M., Martens, G. J. M., Poelmans, G., & Visser, J. E. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9103-8 · Cited by 29
Neurodevelopmental Disorders: Functional Role of Ambra1 in Autism and Schizophrenia
Barbera, L. L., Vedele, F., Nobili, A., D’Amelio, M., & Krashia, P. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1557-7 · Cited by 21
“being pivotal for the elimination of damaged mitochondria [9, 10], its reduction in Ambra1 mice would be expected to affect most severely the mitophagy process, shifting the bal-”
BackgroundMitochondrial Homeostasis Molecules: Regulation by a Trio of Recessive Parkinson’s Disease Genes
Han, J., Kim, J., & Son, J. H. (2014) · Experimental Neurobiology · doi:10.5607/en.2014.23.4.345 · Cited by 21
“Ambra1 is a Parkininteracting protein [27], and mitochondrial depolarization significantly increases the interaction between Parkin and Ambra1; however, Ambra1 has not been found to be ubiquitinated by Parkin.”
BackgroundMeyer, L. M., Koschade, S. E., Vischedyk, J. B., Thölken, M., Gubaš, A., Wegner, M., Başoğlu, M., Knapp, S., Kaulich, M., Eimer, S., et al. (2023) · Autophagy · doi:10.1080/15548627.2023.2230839 · Cited by 24
“Nevertheless, further mitophagy receptors were discovered after the design of our multiplexed screen and thus not included: AMBRA1 (autophagy and beclin 1 regulator 1) [36], cardiolipin [37], NIPSNAP1 (nipsnap homolog 1), and NIPSNAP2 (nipsnap homolog 2) [38].”
BackgroundRole of mitophagy in intervertebral disc degeneration: A narrative review
Wu, Z., Liu, Y., Song, W., Zhou, K., Yan, L., & Zhang, H.-H. (2024) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2024.09.013 · Cited by 18
The multifaceted mitochondrion: An attractive candidate for therapeutic strategies
Strappazzon, F., & Cecconi, F. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.03.007 · Cited by 17
AMBRA1, a Novel BH3-Like Protein
Rita, A. D., & Strappazzon, F. (2016) · International review of cytology · doi:10.1016/bs.ircmb.2016.09.002 · Cited by 18
Targeted proteomics addresses selectivity and complexity of protein degradation by autophagy
Leytens, A., Benítez‐Fernández, R., Jiménez-García, C., Roubaty, C., Stumpe, M., Boya, P., & Dengjel, J. (2024) · Autophagy · doi:10.1080/15548627.2024.2396792 · Cited by 19
Crosstalk between Autophagy and RLR Signaling
Ke, P. (2023) · Cells · doi:10.3390/cells12060956 · Cited by 17
Plant Mitophagy in Comparison to Mammals: What Is Still Missing?
Ren, K., Feng, L., Sun, S., & Zhuang, X. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031236 · Cited by 22
“Additionally, an OMM receptor activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1), by recruiting Beclin1, induces PINK1/Parkin-dependent mitophagy pathway [34] and the receptor-dependent pathway [35].”
BackgroundMitophagy and iron: two actors sharing the stage in age-associated neuronal pathologies
Schiavi, A., Strappazzon, F., & Ventura, N. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111252 · Cited by 22
Implications of Therapy-Induced Selective Autophagy on Tumor Metabolism and Survival
Hughson, L. R. K., Poon, V. I., Spowart, J. E., & Lum, J. J. (2012) · International Journal of Cell Biology · doi:10.1155/2012/872091 · Cited by 18
“One possibility is that Parkin stimulates the generation of autophagy inducing signals from the Beclin1/Vps34 class III PI3K complex by interacting with the autophagy promoting protein, Ambra1 [40].”
BackgroundMitophagy: A double-edged sword in tumor cell death regulation and therapeutic response
Chu, T., Huang, Z., & Ma, W. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152254 · Cited by 14
Hyperactivated mitophagy in hematopoietic stem cells
Yang, C., & Suda, T. (2017) · Nature Immunology · doi:10.1038/s41590-017-0008-8 · Cited by 16
Mitochondrial Regulation by PINK1-Parkin Signaling
Imai, Y. (2012) · ISRN Cell Biology · doi:10.5402/2012/926160 · Cited by 15
AMBRA1-induced mitophagy: A new mechanism to cope with cancer?
Strappazzon, F., & Cecconi, F. (2015) · Molecular & Cellular Oncology · doi:10.4161/23723556.2014.975647 · Cited by 15
“In this context, activating molecule in beclin 1 regulated autophagy (AMBRA1) interacts with PARKIN to enhance mitochondrial clearance.(1) In our study,(2) we identified AMBRA1 as a LIR (LC3-interacting region)-containing protein and found that this motif is essential for the binding between AMBRA1 and LC3 only follow…”
BackgroundResultInfluentialSkeletal Muscle Regeneration in the Mouse
Kyba, M. (2016) · Methods in Molecular Biology · doi:10.1007/978-1-4939-3810-0 · Cited by 15
Mechanism and regulation of mitophagy in liver diseases: a review
Liu, S., Wang, L., Zhu, L., Zhao, T., Han, P., Yan, F., Wang, X., Li, C., Wang, Z., & Yang, B. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1614940 · Cited by 14
Manipulating autophagic degradation in human diseases: from mechanisms to interventions
Zhang, Y., Liu, X., Klionsky, D. J., Lu, B., & Zhong, Q. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac043 · Cited by 14
Moussa, C. E.-H. (2015) · Neurodegenerative Diseases · doi:10.1159/000430888 · Cited by 13
Isolation, Characterization, and Autophagy Function of BECN1-Splicing Isoforms in Cancer Cells
Maheshwari, C., Vidoni, C., Titone, R., Castiglioni, A., Lora, C., Follo, C., & Isidoro, C. (2022) · Biomolecules · doi:10.3390/biom12081069 · Cited by 13
“We checked also AMBRA1 protein levels since AMBRA1 is a BECN1 interactor known to help in the progression of mitophagy [51].”
BackgroundA global view of the miRNA-mitophagy connexion
Strappazzon, F. (2020) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2020.03.006 · Cited by 13
Therapeutic potential of Parkin and its regulation in Parkinson’s disease
Safreena, N., Nair, I. C., & Chandra, G. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116600 · Cited by 11
Tiberti, M., Leo, L. D., Vistesen, M. V., Kuhre, R. S., Cecconi, F., Zio, D. D., & Papaleo, E. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05318-2 · Cited by 13
Tang, X.-Q., Zhang, Y., Liu, X., Li, X., Zhao, H.-R., Cui, H., Shi, Y., Chen, Y.-C., Xu, H., Meng, Z., et al. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174641 · Cited by 12
Mitophagy Regulated by the PINK1-Parkin Pathway
Arano, T., & Imai, Y. (2015) · InTech eBooks · doi:10.5772/61284 · Cited by 14
“Ambra1, an autophagy-promoting protein, is not required for Parkin translocation to depolarized mitochondria [85].”
BackgroundHe, S., Qu, Q., Chen, X., Zhao, L., Jiao, Z.-G., Wan, Z.-T., Kwok, H.-F., & Qu, S.-G. (2024) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2024.115995 · Cited by 11
Metadata
- Authors
- Van Humbeeck, C., Cornelissen, T., Hofkens, H., Mandemakers, W., Gevaert, K., De Strooper, B., & Vandenberghe, W.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- Universitair Ziekenhuis Leuven (BE)
- Corresponding author
- Vandenberghe, W.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-07-13
- Volume
- 31
- Issue
- 28
- Pages
- 10249-10261
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6623066
- OpenAlex
- W2069519643
- Cited by
- 287
- References
- 0
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 23 · 2023: 15 · 2022: 11 · 2021: 22 · 2020: 19 · 2019: 20 · 2018: 11 · 2017: 21 · 2016: 22 · 2015: 33 · 2014: 26 · 2013: 21 · 2012: 22
- FWCI
- 16.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- KU Leuven (P6/28)
- Universiteit Gent
- Vlaamse regering
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- Parkin, AMBRA1, mitophagy, Parkinson's disease, mitochondrial depolarization, class III PI3K, Beclin-1, autophagy, dopaminergic neurons, protein-protein interaction, mitochondrial clearance, ubiquitination
- MeSH terms
- Animals, Autophagy, Brain, Cells, Cultured, Humans, Mitochondria, Neurons, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Mice, Ubiquitination, HEK293 Cells
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