A New Cytosolic Pathway from a Parkinson Disease-associated Kinase, BRPK/PINK1

Murata, Hitoshi; Sakaguchi, Masakiyo; Yu, Jun; Sakaguchi, Yoshihiko; Futami, Junichiro; Yamada, Hidenori; Kataoka, Ken; Huh, Nam

doi:10.1074/jbc.m110.179390

Cited by 111 publications

(123 citation statements)

References 42 publications

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“…Adding to the debate surrounding PINK1 52 topology is the uncertainty about whether this cleaved frag-ment is the mature form of PINK1 endowed with functional roles or is merely a byproduct destined to be degraded [16,[21][22][23].…”

Section: Resultsmentioning

confidence: 99%

Cytosolic cleaved PINK 1 represses P arkin translocation to mitochondria and mitophagy

Fedorowicz

Vries‐Schneider

Rüb³

et al. 2013

EMBO Reports

102

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PINK1 is a mitochondrial kinase proposed to have a role in the pathogenesis of Parkinson's disease through the regulation of mitophagy. Here, we show that the PINK1 main cleavage product, PINK1 52, after being generated inside mitochondria, can exit these organelles and localize to the cytosol, where it is not only destined for degradation by the proteasome but binds to Parkin. The interaction of cytosolic PINK1 with Parkin represses Parkin translocation to the mitochondria and subsequent mitophagy. Our work therefore highlights the existence of two cellular pools of PINK1 that have different effects on Parkin translocation and mitophagy.

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Section: Resultsmentioning

confidence: 99%

Cytosolic cleaved PINK 1 represses P arkin translocation to mitochondria and mitophagy

Fedorowicz

Vries‐Schneider

Rüb³

et al. 2013

EMBO Reports

102

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“…PINK1, that resides at the OMM [186,249] and is also present in the cytosol [250], modulates mitochondrial morphogenesis, distribution, and dynamics and attenuates ROS production in SN DAergic cells [251][252][253][254] (Figure 4). However, the mechanism by which PINK1 or parkin confers neuroprotection is not clear [255].…”

Section: It Improves Mitochondrial Dysfunction Altersmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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“…6). The results of the present and previous studies (15) indicate that PINK1 can be a new target molecule to sensitize resistant bladder cancer cells to Ad-REIC. …”

Section: Discussionmentioning

confidence: 62%

“…Overexpression of wild-type PINK1 protected neuronal cells against various stresses (12), whereas downregulation of PINK1 sensitized neuroblastoma cells to various stresses (13). On the other hand, we showed that PINK1 was expressed at high levels in malignant cancer cells exhibiting an increased metastatic activity (14) and that PINK1 protected cancer cells against various cytotoxic agents through Akt activation (15,16). Martin et al (17) reported that PINK1 is a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers.…”

Section: Introductionmentioning

confidence: 73%

Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1

Jin

Murata²,

Sakaguchi³

et al. 2011

Oncol Rep

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Abstract. REIC/Dkk-3 is a tumor suppressor gene that was first identified as a gene downregulated in association with immortalization of normal human fibroblasts. We have demonstrated that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) showed a tumor-specific killing effect on a wide range of cancers. However, some human cancers, bladder cancers in particular, are resistant to Ad-REIC. In this study, we investigated the combination effect of downregulation of BRPK/PINK1 (PINK1) and Ad-REIC on bladder cancer cells. Five bladder cancer cell lines among six cell lines examined were resistant to Ad-REIC. Among the cell lines, the resistance of two cell lines was probably due to low infection efficiency of the adenovirus. PINK1-specific siRNA remarkably downregulated Bcl-x L and TRAP1 proteins and upregulated BAX protein expression. Finally, downregulation of PINK1 partially sensitized the other three cell lines that were resistant to Ad-REIC. This sensitization was associated with increasing production of reactive oxygen species (ROS). These results indicate that PINK1 is one of the key molecules for the mitochondrial protection system and that PINK1 can be a new target molecule to sensitize bladder cancer cells that are resistant to Ad-REIC.

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A New Cytosolic Pathway from a Parkinson Disease-associated Kinase, BRPK/PINK1

Cited by 111 publications

References 42 publications

Cytosolic cleaved PINK 1 represses P arkin translocation to mitochondria and mitophagy

Cytosolic cleaved PINK 1 represses P arkin translocation to mitochondria and mitophagy

The role of α-synuclein in neurodegeneration — An update

Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1

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