Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain

Kim, Se Jung; Sung, Jee Young; Um, Ji Won; Hattori, Nobutaka; Mizuno, Yoshikuni; Tanaka, Keiji; Paik, Seung R.; Kim, Jongsun; Chung, Kwang Chul

doi:10.1074/jbc.m306017200

Cited by 72 publications

(50 citation statements)

References 46 publications

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“…47 Activation of calpain was shown to protect from apoptosis by inducing parkin-mediated cleavage of alphasynuclein in neurons. 48 In addition, calpains were shown to activate survival through the erk pathways in neurons, 49 and NF-kB survival pathway after TNF treatment. 24 On the other hand, calpain can cleave and activate caspase 12 50 and calpain-mediated cleavage of bax to a p18 form accelerates apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Ceramide triggers an NF-κB-dependent survival pathway through calpain

et al. 2005

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We have shown that C2 ceramide, a cell-permeable analog of this lipid second messenger, triggers an NF-jB dependent survival pathway that counteracts cell death. Activation of NF-jB and subsequent induction of prosurvival genes relies on calpain activity and is prevented on silencing of the calpain small subunit (Capn4) that is required for the function of ubiquitous calpains. We have demonstrated that p105 (NFjB1) and its proteolytic product p50 can be targets of microand milli-calpain in vitro and that a p50 deletion mutant, lacking both the N-and the C-terminal ends, is resistant to calpain-mediated degradation. Capn4 silencing results in stabilization of endogenous p105 and p50 in diverse human cell lines. Furthermore, p105 processing and activation of NFjB survival genes in response to C2 ceramide is impaired in Capn4À/À mouse embryonic fibroblasts defective in calpain activity. Altogether, these data argue for the existence of a ceramide-calpain-NF-jB axis with prosurvival functions.

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Section: Discussionmentioning

confidence: 99%

Ceramide triggers an NF-κB-dependent survival pathway through calpain

et al. 2005

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“…Based on our previous report (17), in which Parkin was shown to cleave intracellular ␣-synuclein inclusions via calpain activation, we also tested the effect of the calpain inhibitor, calpeptin, to confirm the involvement of calpain in the Parkin-mediated degradation of RanBP2. When SH-SY5Y cells were transiently transfected with Parkin, followed by the stimulation of lactacystin, the reduction of endogenous RanBP2 levels was remarkably blocked, as compared with the control cells that were FIGURE 2.…”

Section: Yeast Two-hybrid Assay For the Identification Of New Parkin mentioning

confidence: 99%

“…Several substrates of Parkin have been reported to date, including cell division control-related protein-1 (CDCrel-1; Ref. 13), synphilin-1 (14), Pael-R (10, 15), ␣-synuclein (16,17), the p38 subunit of aminoacyl-tRNA synthetase (18), cyclin E (19), ␣/␤-tubulin (20), and polyglutamine protein (21).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Parkin Ubiquitinates and Promotes the Degradation of RanBP2

Min

Rhim

et al. 2006

Journal of Biological Chemistry

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Parkinson disease (PD) is a common neurodegenerative disorder, which involves the deterioration of dopaminergic neurons in the pars compacta of the substantia nigra. The etiology of PD is still unknown, but recent identification of mutations in familial cases of PD has advanced the understanding of the molecular mechanisms of this neurological disease. Mutations in the parkin gene, which encodes for ubiquitin-protein ligase (E3), have been implicated in autosomal recessive juvenile Parkinsonism, an early onset and common familial form of PD. Here we reported that Parkin selectively binds to RanBP2, which is localized in the cytoplasmic filament of the nuclear pore complex and belongs to the small ubiquitin-related modifier E3 ligase family. We also demonstrated that RanBP2 becomes a target for Parkin E3 ubiquitin-ligase and is processed via Parkin-mediated ubiquitination and subsequent proteasomal degradation. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2. Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkinmediated ubiquitination and proteasomal pathways. Parkinson disease (PD)2 is a major neurodegenerative disease characterized by a distinct set of movement disorders, including muscle rigidity, tremor, and bradykinesia (1). In PD, the level of dopamine is decreased in the striatum, most severely in the putamen. This is largely a result of the deterioration of dopaminergic neurons in the substantia nigra pars compacta (2-4). The etiology of PD remains poorly understood, but several genetic loci have been implicated in the pathogenesis of familial forms of PD. First, two missense mutations of ␣-synuclein have been linked to a rare dominant form of PD (5). Second, parkin has been identified as the causative gene of early onset autosomal recessive juvenile parkinsonism (AR-JP) (6), and a missense mutation in the ubiquitin (Ub) C-terminal hydrolase L1 appears to be responsible for a dominant form of PD (7). Most recently, mutations in DJ-1 and PTENinduced putative kinase-1 have been correlated with the incidences of familial PD (8, 9).The structure of Parkin contains a C-terminal RING-IBR-RING motif and an N-terminal region with homology to ubiquitin (10 -12). Proteins destined to degrade in the proteasomes are subject to covalent modification by ubiquitin as a small protein tag. Ubiquitination proceeds through a sequential enzymatic reaction composed of ubiquitinactivating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3) (13). Based on the previous findings that numerous proteins with RING finger motifs have E3 ubiquitin-ligase activity, several studies have revealed that Parkin has an ubiquitin E3 ligase activity. The exquisite specificity for the proteins to be ubiquitinated is usually determined by a diverse family of E3s with a specific E2.Based on the functional role of Parkin, it can be surmised that the loss of Parkin resul...

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“…2). Calpain I (26,39) and perturbations in the ubiquitin-proteasome (31, 37, 54, 55) system have been implicated in the pathogenesis of Parkinson disease and related pathologies. It seems plausible, therefore, that nitration of ␣-syn could disturb the balance between lipid binding and removal of the modified protein in favor of its accumulation and aggregation in the cytosol.…”

Section: Chromatographic Separation Of ␣-Syn Modified Species-mentioning

confidence: 99%

Functional Consequences of α-Synuclein Tyrosine Nitration

Hodara

Norris

Giasson

et al. 2004

Journal of Biological Chemistry

242

120

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Previous studies have shown the presence of nitrated ␣-synuclein (␣-syn) in human Lewy bodies and other ␣-syn inclusions. Herein, the effects of tyrosine nitration on ␣-syn fibril formation, lipid binding, chaperone-like function, and proteolytic degradation were systematically examined by employing chromatographically isolated nitrated monomeric, dimeric, and oligomeric ␣-syn. Nitrated ␣-syn monomers and dimers but not oligomers accelerated the rate of fibril formation of unmodified ␣-syn when present at low concentrations. Immunoelectron microscopy revealed that nitrated monomers and dimers are incorporated into the fibrils. However, the purified nitrated ␣-syn monomer by itself was unable to form fibrils. Nitration of the tyrosine residue at position 39 was largely responsible for decreased binding of nitrated monomeric ␣-syn to synthetic vesicles, which correlated with an impairment of the nitrated protein to adopt ␣-helical conformation in the presence of liposomes. The chaperone-like activity of ␣-syn was not inhibited by nitration or oxidation. Furthermore, the 20 S proteasome and calpain I degraded nitrated monomeric ␣-syn, although at a slower rate compared with control ␣-syn. Collectively, these data suggest that post-translational modification of ␣-syn by nitration can promote the formation of intracytoplasmic inclusions that constitute the hallmark of Parkinson disease and other synucleinopathies. ␣-Synuclein (␣-syn)1 is a 140-amino acid, natively unfolded, heat-stable, and soluble protein that is localized in the presynaptic terminals of neurons in the central nervous system (1-4), where it may regulate the release of a reserved pool of synaptic vesicles (5). ␣-syn interacts with a number of proteins affecting the activities of some enzymes such as phospholipase D2 (6) and tyrosine hydroxylase (7), and it can function as a chaperone-like protein (8 -10). However, under pathological conditions ␣-syn can aggregate into intracellular proteinaceous inclusions such as Lewy bodies (LBs) and Lewy neurites found in the brains of patients with Parkinson disease and other related disorders (11)(12)(13)(14). Immunoelectron microscopy and thioflavin S fluorescence of LBs has revealed the presence of ␣-syn fibrils, indicating the ability of the protein to undergo organized fibril assembly (11-13). The formation of ␣-syn fibrils has been extensively studied in vitro, confirming the formation of dimers, oligomers, protofibrillar structures, and mature linear fibers (15)(16)(17)(18)(19), although the precise sequence of events that leads to protein aggregation in vivo is not well defined.Post-translational modifications of ␣-syn may be responsible for the formation of proteinaceous inclusions. Antibodies that specifically recognize tyrosine-nitrated epitopes in ␣-syn decorate ␣-syn fibrils in LBs and Lewy neurites (20). Although these observations indicate that ␣-syn is a target for reactive nitrogen species in vivo, it remains unclear whether this posttranslational modification is a primary event that leads to agg...

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Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain

Cited by 72 publications

References 46 publications

Ceramide triggers an NF-κB-dependent survival pathway through calpain

Ceramide triggers an NF-κB-dependent survival pathway through calpain

Parkin Ubiquitinates and Promotes the Degradation of RanBP2

Functional Consequences of α-Synuclein Tyrosine Nitration

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