Genomes and Genes
Gene Symbol: Park2
Description: Parkinson disease (autosomal recessive, juvenile) 2, parkin
Alias: PRKN, E3 ubiquitin-protein ligase parkin, parkin RBR E3 ubiquitin-protein ligase, parkin protein
- Ekholm Reed S, Goldberg M, Schlossmacher M, Reed S. Parkin-dependent degradation of the F-box protein Fbw7? promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1. Mol Cell Biol. 2013;33:3627-43 pubmed publisher..b>PARK2, encoding the ubiquitin ligase parkin, is the most frequently mutated gene in hereditary Parkinson's disease...
- Chan N, Salazar A, Pham A, Sweredoski M, Kolawa N, Graham R, et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet. 2011;20:1726-37 pubmed publisher..These results indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates. ..
- Rodriguez Navarro J, Casarejos M, Menéndez J, Solano R, Rodal I, Gomez A, et al. Mortality, oxidative stress and tau accumulation during ageing in parkin null mice. J Neurochem. 2007;103:98-114 pubmed..This study could help to explain the effects of ageing in patients with genetic risks for Parkinson's disease. ..
- Pawlyk A, Giasson B, Sampathu D, Perez F, Lim K, Dawson V, et al. Novel monoclonal antibodies demonstrate biochemical variation of brain parkin with age. J Biol Chem. 2003;278:48120-8 pubmed
- Sato S, Chiba T, Sakata E, Kato K, Mizuno Y, Hattori N, et al. 14-3-3eta is a novel regulator of parkin ubiquitin ligase. EMBO J. 2006;25:211-21 pubmed..Our findings indicate that 14-3-3eta is a regulator that functionally links parkin and alpha-SN. The alpha-SN-positive and 14-3-3eta-negative control of parkin activity sheds new light on the pathophysiological roles of parkin. ..
- Kitada T, Asakawa S, Minoshima S, Mizuno Y, Shimizu N. Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene. Mamm Genome. 2000;11:417-21 pubmed..The amino acid sequence of mouse parkin protein exhibits 83...
- Khandelwal P, Herman A, HOE H, Rebeck G, Moussa C. Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum Mol Genet. 2011;20:2091-102 pubmed publisher..Parkin-mediated clearance of ubiquitinated A? may act in parallel with autophagy to clear molecular debris and defective mitochondria and restore neurotransmitter balance. ..
- Perez F, Palmiter R. Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci U S A. 2005;102:2174-9 pubmed..To determine whether mutations in the mouse parkin gene (Park2) also result in a parkinsonian phenotype, we generated mice with a targeted deletion of parkin exon 2...
- Ding W, Ni H, Li M, Liao Y, Chen X, Stolz D, et al. Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J Biol Chem. 2010;285:27879-90 pubmed publisher..Our work thus distinguished the molecular events responsible for the different phases of mitophagy and placed Nix upstream of the events. ..
- Fallon L, Bélanger C, Corera A, Kontogiannea M, Regan Klapisz E, Moreau F, et al. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nat Cell Biol. 2006;8:834-42 pubmed..Considering the role of Akt in neuronal survival, our results have broad new implications for understanding the pathogenesis of Parkinson's disease. ..
- Jiang H, Ren Y, Yuen E, Zhong P, Ghaedi M, Hu Z, et al. Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun. 2012;3:668 pubmed publisher..Thus, the study provides novel targets and a physiologically relevant screening platform for disease-modifying therapies of PD. ..
- Shiba Fukushima K, Imai Y, Yoshida S, Ishihama Y, Kanao T, Sato S, et al. PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep. 2012;2:1002 pubmed publisher..Our study partly uncovers the molecular mechanism underlying the PINK1-dependent mitochondrial translocation and activation of Parkin as an initial step of mitophagy. ..
- Kitada T, Pisani A, Karouani M, Haburcak M, Martella G, Tscherter A, et al. Impaired dopamine release and synaptic plasticity in the striatum of parkin-/- mice. J Neurochem. 2009;110:613-21 pubmed publisher..However, it remains unclear how loss of Parkin protein causes dopaminergic dysfunction and nigral neurodegeneration...
- Ko H, von Coelln R, Sriram S, Kim S, Chung K, Pletnikova O, et al. Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. J Neurosci. 2005;25:7968-78 pubmed..Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD. ..
- Lonskaya I, Hebron M, Desforges N, Franjie A, Moussa C. Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance. EMBO Mol Med. 2013;5:1247-62 pubmed publisher..These data suggest that decreased parkin solubility impedes parkin-Beclin-1 interaction and amyloid clearance. We identified two FDA-approved anti-cancer drugs as potential treatment for AD. ..
- Joselin A, Hewitt S, Callaghan S, Kim R, Chung Y, Mak T, et al. ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons. Hum Mol Genet. 2012;21:4888-903 pubmed publisher..These results not only highlight the presence of a Parkin/Pink1-mediated pathway of mitochondrial quality control (MQC) in neurons, they also delineate a complex reciprocal relationship between DJ-1 and the Pink1/Parkin pathway of MQC. ..
- Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier C, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol. 2010;189:211-21 pubmed publisher..Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD. ..
- Sterky F, Lee S, Wibom R, Olson L, Larsson N. Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo. Proc Natl Acad Sci U S A. 2011;108:12937-42 pubmed publisher..We also show that anterograde axonal transport of mitochondria is impaired in respiratory chain-deficient DA neurons, leading to a decreased supply of mitochondria to the axonal terminals. ..
- Rothfuss O, Fischer H, Hasegawa T, Maisel M, Leitner P, Miesel F, et al. Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair. Hum Mol Genet. 2009;18:3832-50 pubmed publisher..Our data indicate a novel role for parkin in directly supporting mitochondrial function and protecting mitochondrial genomic integrity from oxidative stress. ..
- Palacino J, Sagi D, Goldberg M, Krauss S, Motz C, Wacker M, et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004;279:18614-22 pubmed
- Sato S, Chiba T, Nishiyama S, Kakiuchi T, Tsukada H, Hatano T, et al. Decline of striatal dopamine release in parkin-deficient mice shown by ex vivo autoradiography. J Neurosci Res. 2006;84:1350-7 pubmed..Our results suggest that dopaminergic neurons could behave abnormally before neuronal death. ..
- Imam S, Zhou Q, Yamamoto A, Valente A, Ali S, Bains M, et al. Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease. J Neurosci. 2011;31:157-63 pubmed publisher..Moreover, inhibition of c-Abl offers new therapeutic opportunities for blocking PD progression. ..
- Staropoli J, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A. Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron. 2003;37:735-49 pubmed..Furthermore, parkin overexpression attenuates the accumulation of cyclin E in toxin-treated primary neurons, including midbrain dopamine neurons, and protects them from apoptosis. ..
- Periquet M, Corti O, Jacquier S, Brice A. Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function. J Neurochem. 2005;95:1259-76 pubmed..This study provides clues into possible compensatory mechanisms that protect dopaminergic neurones from death in parkin KO mice and may help us understand the preclinical deficits observed in parkin-related parkinsonism. ..
- Hanson J, Orr A, Madison D. Altered hippocampal synaptic physiology in aged parkin-deficient mice. Neuromolecular Med. 2010;12:270-6 pubmed publisher..homozygous parkin deficiency suggest compensatory responses to genetic abnormalities could play an important role during the development of pathology in response to parkin deficiency. ..
- von Coelln R, Thomas B, Savitt J, Lim K, Sasaki M, Hess E, et al. Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci U S A. 2004;101:10744-9 pubmed..Autosomal-recessive juvenile Parkinsonism (ARJP) is caused by mutations in the PARK2 gene coding for parkin and constitutes the most common familial form of PD...
- Rodriguez Navarro J, Gomez A, Rodal I, Perucho J, Martinez A, Furió V, et al. Parkin deletion causes cerebral and systemic amyloidosis in human mutated tau over-expressing mice. Hum Mol Genet. 2008;17:3128-43 pubmed publisher..PK(-/-)/Tau(VLW) mice provide a link between the two proteins more important for the pathogenesis of Alzheimer disease. ..
- Chen Y, Dorn G. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science. 2013;340:471-5 pubmed publisher..Thus, Mfn2 functions as a mitochondrial receptor for Parkin and is required for quality control of cardiac mitochondria. ..
- Um J, Min D, Rhim H, Kim J, Paik S, Chung K. Parkin ubiquitinates and promotes the degradation of RanBP2. J Biol Chem. 2006;281:3595-603 pubmed..Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkin-mediated ubiquitination and proteasomal pathways. ..
- Hebron M, Lonskaya I, Sharpe K, Weerasinghe P, Algarzae N, Shekoyan A, et al. Parkin ubiquitinates Tar-DNA binding protein-43 (TDP-43) and promotes its cytosolic accumulation via interaction with histone deacetylase 6 (HDAC6). J Biol Chem. 2013;288:4103-15 pubmed publisher..Parkin and TDP-43 formed a multiprotein complex with HDAC6, perhaps to mediate TDP-43 translocation. In conclusion, Parkin ubiquitinates TDP-43 and facilitates its cytosolic accumulation through a multiprotein complex with HDAC6. ..
- Chen D, Gao F, Li B, Wang H, Xu Y, Zhu C, et al. Parkin mono-ubiquitinates Bcl-2 and regulates autophagy. J Biol Chem. 2010;285:38214-23 pubmed publisher..Moreover, overexpression of parkin enhances the interactions between Bcl-2 and Beclin 1. Our results provide evidence that parkin mono-ubiquitinates Bcl-2 and regulates autophagy via Bcl-2. ..
- Joch M, Ase A, Chen C, MacDonald P, Kontogiannea M, Corera A, et al. Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. Mol Biol Cell. 2007;18:3105-18 pubmed
- Stichel C, Augustin M, Kuhn K, Zhu X, Engels P, Ullmer C, et al. Parkin expression in the adult mouse brain. Eur J Neurosci. 2000;12:4181-94 pubmed..The Parkin protein expression profile was studied using immunohistochemistry and Western blot analysis and was compared with that ..
- Son J, Kawamata H, Yoo M, Kim D, Lee Y, Kim S, et al. Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic neurons. J Neurochem. 2005;94:1040-53 pubmed..These data suggest that a threshold level of Septin 5 accumulation is required for DAergic cell loss and that l-DOPA-responsive motor deficits can occur even in the presence of elevated DA. ..
- Petrucelli L, O Farrell C, Lockhart P, Baptista M, Kehoe K, Vink L, et al. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron. 2002;36:1007-19 pubmed..Therefore, parkin and alpha-synuclein are linked by common effects on a pathway associated with selective cell death in catecholaminergic neurons. ..
- Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou Y, et al. p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells. 2010;15:887-900 pubmed publisher..Thus, p62 is required for ubiquitylation-dependent clustering of damaged mitochondria, which resembles p62-mediated 'aggresome' formation of misfolded/unfolded proteins after ubiquitylation. ..
- Kurtenbach S, Wewering S, Hatt H, Neuhaus E, Lübbert H. Olfaction in three genetic and two MPTP-induced Parkinson's disease mouse models. PLoS ONE. 2013;8:e77509 pubmed publisher..Further we show that intranasal MPTP application can cause functional damage of the olfactory epithelium. ..
- Duplan E, Sevalle J, Viotti J, Goiran T, Bauer C, Renbaum P, et al. Parkin differently regulates presenilin-1 and presenilin-2 functions by direct control of their promoter transcription. J Mol Cell Biol. 2013;5:132-42 pubmed publisher..Overall, our data delineate a promoter responsive element targeted by parkin that drives differential regulation of presenilin-1 and presenilin-2 transcription with functional consequences for ?-secretase activity and cell death. ..
- Perucho J, Casarejos M, Rubio I, Rodriguez Navarro J, Gomez A, Ampuero I, et al. The effects of parkin suppression on the behaviour, amyloid processing, and cell survival in APP mutant transgenic mice. Exp Neurol. 2010;221:54-67 pubmed publisher..We proposed that partial and total suppression of parkin triggers compensatory mechanisms, such as chaperone overexpression and increased autophagy, which improved the behavioural and cellular phenotype of APP(swe) mice. ..
- Zhu X, Maskri L, Herold C, Bader V, Stichel C, Gunturkun O, et al. Non-motor behavioural impairments in parkin-deficient mice. Eur J Neurosci. 2007;26:1902-11 pubmed
- Kubli D, Zhang X, Lee Y, Hanna R, Quinsay M, Nguyen C, et al. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. J Biol Chem. 2013;288:915-26 pubmed publisher..Interestingly, Parkin protein levels and mitochondrial autophagy (mitophagy) were rapidly increased in the border zone of the infarct in ..
- Kühn K, Zhu X, Lübbert H, Stichel C. Parkin expression in the developing mouse. Brain Res Dev Brain Res. 2004;149:131-42 pubmed..Our results show that parkin expression is correlated with cell maturation and suggests an important physiological role of parkin in neurons that is at no time limited to the dopaminergic system. ..
- Yoshii S, Kishi C, Ishihara N, Mizushima N. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem. 2011;286:19630-40 pubmed publisher..These results suggest that Parkin regulates degradation of outer and inner mitochondrial membrane proteins differently through proteasome- and mitophagy-dependent pathways. ..
- Ko H, Lee Y, Shin J, Karuppagounder S, Gadad B, Koleske A, et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proc Natl Acad Sci U S A. 2010;107:16691-6 pubmed publisherMutations in PARK2/Parkin, which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinson disease (PD)...
- Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605-8 pubmed..Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product 'Parkin'. ..
- Zhang C, Lin M, Wu R, Wang X, Yang B, Levine A, et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci U S A. 2011;108:16259-64 pubmed publisherRegulation of energy metabolism is a novel function of p53 in tumor suppression. Parkin (PARK2), a Parkinson disease-associated gene, is a potential tumor suppressor whose expression is frequently diminished in tumors...
- Shin J, Ko H, Kang H, Lee Y, Lee Y, Pletinkova O, et al. PARIS (ZNF746) repression of PGC-1? contributes to neurodegeneration in Parkinson's disease. Cell. 2011;144:689-702 pubmed publisher..The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation. ..
- Schmidt S, Linnartz B, Mendritzki S, Sczepan T, Lübbert M, Stichel C, et al. Genetic mouse models for Parkinson's disease display severe pathology in glial cell mitochondria. Hum Mol Genet. 2011;20:1197-211 pubmed publisher..Such transgenic astrocytes fail to influence neuronal differentiation, reflecting an important role that glia may play in PD pathogenesis. ..
- Casarejos M, Menendez J, Solano R, Rodriguez Navarro J, Garcia de Yebenes J, Mena M. Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline. J Neurochem. 2006;97:934-46 pubmed..PK-KO mice were more susceptible than WT to ROT and the combined effects of Park-2 suppression and ROT reproduced the cellular events observed in Parkinson's disease. These events were prevented by minocycline. ..
- Trempe J, Chen C, Grenier K, Camacho E, Kozlov G, McPherson P, et al. SH3 domains from a subset of BAR proteins define a Ubl-binding domain and implicate parkin in synaptic ubiquitination. Mol Cell. 2009;36:1034-47 pubmed publisher..The findings identify a pathway for the recruitment of synaptic substrates to parkin with the potential to explain the defects in synaptic transmission observed in recessive forms of PD. ..
- Yao D, Gu Z, Nakamura T, Shi Z, Ma Y, Gaston B, et al. Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc Natl Acad Sci U S A. 2004;101:10810-4 pubmed..These findings may thus provide a molecular link between free radical toxicity and protein accumulation in sporadic Parkinson's disease. ..
- Klinkenberg M, Gispert S, Dominguez Bautista J, Braun I, Auburger G, Jendrach M. Restriction of trophic factors and nutrients induces PARKIN expression. Neurogenetics. 2012;13:9-21 pubmed publisher..The corresponding threefold starvation induction of PARKIN protein was limited by its translocation to lysosomes...
- Itier J, Ibanez P, Mena M, Abbas N, Cohen Salmon C, Bohme G, et al. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet. 2003;12:2277-91 pubmed
- Wang H, Imai Y, Inoue H, Kataoka A, Iita S, Nukina N, et al. Pael-R transgenic mice crossed with parkin deficient mice displayed progressive and selective catecholaminergic neuronal loss. J Neurochem. 2008;107:171-85 pubmed publisher..parkin-ko/Pael-R-tg mice represents an AR-JP mouse model displaying chronic and selective loss of catecholaminergic neurons. ..
- Johnson B, Berger A, Cortese G, LaVoie M. The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax. Proc Natl Acad Sci U S A. 2012;109:6283-8 pubmed publisherAutosomal recessive loss-of-function mutations within the PARK2 gene functionally inactivate the E3 ubiquitin ligase parkin, resulting in neurodegeneration of catecholaminergic neurons and a familial form of Parkinson disease...
- Aguiar A, Tristao F, Amar M, Chevarin C, Lanfumey L, Mongeau R, et al. Parkin-knockout mice did not display increased vulnerability to intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neurotox Res. 2013;24:280-7 pubmed publisher..These findings also suggest that the development of familial parkin-linked PD is not associated with exposure to environmental factors that specifically affects the dopaminergic system. ..