Parkin Mediates Neuroprotection through Activation of IκB Kinase/Nuclear Factor-κB Signaling

Henn, Iris H.; Bouman, Lena; Schlehe, Julia S.; Schlierf, Anita; Schramm, Julia E.; Wegener, Elmar; Nakaso, Kazuhiro; Culmsee, Carsten; Berninger, Benedikt; Krappmann, Daniel; Tatzelt, Jörg; Winklhofer, Konstanze F.

doi:10.1523/jneurosci.5537-06.2007

Cited by 173 publications

(175 citation statements)

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“…We previously observed that the complex I inhibitor rotenone induces an upregulation of parkin mRNA and protein levels. 18 CCCP has recently been shown to cause the translocation of parkin to damaged mitochondria, which are then removed by autophagy. 19 We, therefore addressed the question whether CCCP might also have an impact on the transcriptional regulation of parkin.…”

Section: Resultsmentioning

confidence: 99%

“…SDS-PAGE and western blotting was described earlier. 18 Antigens were detected with the enhanced chemiluminescence detection system (Amersham Biosciences, Freiburg, Germany) or the Immobilon Western chemoluminiscent HRP substrate (Millipore).…”

Section: Discussionmentioning

confidence: 99%

“…Real-time RT-PCR was performed, as described before. 18 Briefly, SH-SY5Y cells were incubated with 1 mM TG, 2 mg/ml TM, 10 mM CCCP or 10 mM SP600125 for the indicated time. Total cellular RNA was isolated according to manufacturer's instructions (RNaesy mini kit, QIAGEN, Hilden, Germany).…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear extracts were prepared as described earlier. 18 For the binding reaction, 10 mg of extracts were incubated with 10 mM HEPES (pH 7.9), 50 mM NaCl, 5 mM MgCl 2 , 2 mM DTT, 0.1 mM EDTA, 5% glycerol, 10 mg BSA, 2 mg poly(dI-dC) and 0.2 ng (20 000 cpm) of 32 P-labeled, double-stranded park oligonucleotide (5 0 -CCCCGGTGACGTAAGATTGC-3 0 ) in a final volume of 20 ml. For supershift assays, 0.2 mg of the ATF4 antibody or 2 mg of the c-Jun (N) sc45X antibody, for competition experiments 50 ng (100 Â ) of cold-park oligonucleotide was added to the binding reaction.…”

Section: Discussionmentioning

confidence: 99%

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Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress

et al. 2010

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Loss of parkin function is responsible for the majority of autosomal recessive parkinsonism. Here, we show that parkin is not only a stress-protective, but also a stress-inducible protein. Both mitochondrial and endoplasmic reticulum (ER) stress induce an increase in parkin-specific mRNA and protein levels. The stress-induced upregulation of parkin is mediated by ATF4, a transcription factor of the unfolded protein response (UPR) that binds to a specific CREB/ATF site within the parkin promoter. Interestingly, c-Jun can bind to the same site, but acts as a transcriptional repressor of parkin gene expression. We also present evidence that mitochondrial damage can induce ER stress, leading to the activation of the UPR, and thereby to an upregulation of parkin expression. Vice versa, ER stress results in mitochondrial damage, which can be prevented by parkin. Notably, the activity of parkin to protect cells from stress-induced cell death is independent of the proteasome, indicating that proteasomal degradation of parkin substrates cannot explain the cytoprotective activity of parkin. Our study supports the notion that parkin has a role in the interorganellar crosstalk between the ER and mitochondria to promote cell survival under stress, suggesting that both ER and mitochondrial stress can contribute to the pathogenesis of Parkinson's disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress

et al. 2010

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“…The realization that these proteins are in a single pathway, with PINK1 acting upstream of Parkin to influence mitochondrial properties, was a critical step in uncovering the underlying pathological mechanisms of PD (5)(6)(7). This pathway can trigger the selective autophagy of damaged mitochondria, termed mitophagy (8,9), but additional cellular functions have also been indicated for PINK1 and Parkin (10)(11)(12)(13)(14)(15). Much, however, remains unclear about how the PINK1/Parkin pathway is regulated.…”

mentioning

confidence: 99%

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

119

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The PTEN-induced putative kinase 1 (PINK1)/Parkin pathway can tag damaged mitochondria and trigger their degradation by mitophagy. Before the onset of mitophagy, the pathway blocks mitochondrial motility by causing Miro degradation. PINK1 activates Parkin by phosphorylating both Parkin and ubiquitin. PINK1, however, has other mitochondrial substrates, including Miro (also called RhoT1 and -2), although the significance of those substrates is less clear. We show that mimicking PINK1 phosphorylation of Miro on S156 promoted the interaction of Parkin with Miro, stimulated Miro ubiquitination and degradation, recruited Parkin to the mitochondria, and via Parkin arrested axonal transport of mitochondria. Although Miro S156E promoted Parkin recruitment it was insufficient to trigger mitophagy in the absence of broader PINK1 action. In contrast, mimicking phosphorylation of Miro on T298/T299 inhibited PINK1-induced Miro ubiquitination, Parkin recruitment, and Parkin-dependent mitochondrial arrest. The effects of the T298E/T299E phosphomimetic were dominant over S156E substitution. We propose that the status of Miro phosphorylation influences the decision to undergo Parkin-dependent mitochondrial arrest, which, in the context of PINK1 action on other substrates, can restrict mitochondrial dynamics before mitophagy.is the second most common neurodegenerative disorder, and is closely linked to mitochondrial dysfunction (1, 2). Two hereditary forms of recessive PD are caused by mutations in PINK1 (PTEN-induced putative kinase 1), a Ser/Thr mitochondrial kinase, and Parkin, a cytosolic E3 ubiquitin ligase (3, 4). The realization that these proteins are in a single pathway, with PINK1 acting upstream of Parkin to influence mitochondrial properties, was a critical step in uncovering the underlying pathological mechanisms of PD (5-7). This pathway can trigger the selective autophagy of damaged mitochondria, termed mitophagy (8, 9), but additional cellular functions have also been indicated for PINK1 and Parkin (10-15). Much, however, remains unclear about how the PINK1/Parkin pathway is regulated.In current models of PINK1/Parkin mitophagy (reviewed in ref. 1), healthy mitochondria import a PINK1 precursor constitutively to the inner membrane, where it is cleaved (16-18). The cleaved form then returns to the cytoplasm and is degraded by the N-end rule pathway (19). Mitochondrial depolarization, or protein misfolding in the matrix of energized mitochondria (20), prevent the import and degradation of PINK1, resulting in the accumulation of PINK1 on the outer mitochondrial membrane (OMM) (9,21,22). Once on the OMM, PINK1 kinase activity recruits Parkin from the cytosol (8, 9). Although Parkin adopts a self-inhibited conformation in solution (23-25), it becomes fully activated in a PINK1-dependent manner on the mitochondria (9, 21). Parkin ubiquitinates numerous proteins of the OMM (26, 27), and thereby recruits autophagy-related proteins to the damaged mitochondrion for autophagosome assembly (28-30).How PINK1 recruits and activa...

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The M458L missense mutation disrupts the catalytic properties of Parkin

Yun

Park

et al. 2017

FEBS Letters

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Parkin encodes an E3 ubiquitin ligase, and mutations affecting its catalytic potential are implicated in autosomal recessive Parkinson's disease (PD). The M458L mutation of parkin and its enzymatic effects require characterization. Therefore, we examined the enzymatic activity of Parkin with M458L mutation. We show that the M458L mutant retains its autoubiquitination potential in vitro but not in cells. Fas-associated factor 1 and p38 (substrates of Parkin) are able to bind to the M458L mutant in cells; however, these Parkin substrates are not ubiquitinated and degraded in M458L mutant-transfected cells. Moreover, M458L mutant fails to protect the mitochondria against hydrogen peroxide leading to cell death. Considering the role of mitochondrial dysfunction in PD pathogenesis, our results imply a causative role for the M458L mutation in neurodegeneration.

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Parkin Mediates Neuroprotection through Activation of IκB Kinase/Nuclear Factor-κB Signaling

Cited by 173 publications

References 49 publications

Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress

Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

The M458L missense mutation disrupts the catalytic properties of Parkin

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