PARK7 DJ-1 protects against degeneration of nigral dopaminergic neurons in Parkinson’s disease rat model

Inden, Masatoshi; Taira, Takahiro; Kitamura, Yoshihisa; Yanagida, Takashi; Tsuchiya, Daiju; Takata, Kazuyuki; Yanagisawa, Daijiro; Nishimura, Kaneyasu; Taniguchi, Takashi; Kiso, Yoshiaki; Yoshimoto, Kanji; Agatsuma, Tomohiro; Koide-Yoshida, Shizuyo; Iguchi‐Ariga, Sanae M.M.; Shimohama, Shun; Ariga, Hiroyoshi

doi:10.1016/j.nbd.2006.06.004

Cited by 165 publications

(133 citation statements)

References 63 publications

Supporting

Mentioning

129

Contrasting

Order By: Relevance

“…As ApiCCT1 r does not contain a known nuclear localization signal (32), perhaps the ability to penetrate membranes similar to CPPs might explain the ability of ApiCCT1 r to cofractionate with nuclear proteins. Alternatively, the small size of this chaperone domain would allow it to passively diffuse through the nuclear pore (33). The finding that exogenous ApiCCT1 r delivery can be taken up by cells and localizes to both the cytosol and nucleus are highly significant given that both compartments appear to contribute to pathogenic effects mediated by chronic mHTT expression (34), in particular nuclear accumulation of mHtt exerts toxic effects (1, 12, 17, 18).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, there is support for the feasibility of direct protein delivery in vivo with administration of DJ-1 protein to the brains of 6-Hydroxydopamine (6-OHDA) lesioned rat models of Parkinson's disease resulting in neuroprotective outcomes (33,37). Further optimization to increase the efficiency of ApiCCT1 r transduction into cells and nuclei might also increase the potency of ApiCCT1 r as a therapeutic reagent and is under current investigation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes

Sontag

Joachimiak

Tan

et al. 2013

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

View full text Add to dashboard Cite

Aggregation of misfolded proteins is characteristic of a number of neurodegenerative diseases, including Huntington disease (HD). The CCT/TRiC (chaperonin containing TCP-1/TCP-1 ring) chaperonin complex can inhibit aggregation and cellular toxicity induced by expanded repeat Huntingtin (mHtt) fragments. The substratebinding apical domain of CCT/TRiC subunit CCT1, ApiCCT1, is sufficient to inhibit aggregation of expanded repeat mHtt fragments in vitro, providing therapeutic promise for HD. However, a key hurdle in considering ApiCCT1 as a potential treatment is in delivery. Because ApiCCT1 has a region of similarity to the HIV Tat protein cell-transduction domain, we tested whether recombinant ApiCCT1 (ApiCCT1 r ) protein could enter cells following exogenous delivery and modulate an established panel of mHtt-mediated cell-based phenotypes. Cell fractionation studies demonstrate that exogenous ApiCCT1 r can penetrate cell membranes and can localize to the nucleus, consistent with a strategy that can target both cytosolic and nuclear pathogenic events in HD. ApiCCT1 r application does indeed modulate HD cellular phenotypes by decreasing formation of visible inclusions, fibrillar oligomers, and insoluble mHtt derived from expression of a truncated mHtt exon 1 fragment. ApiCCT1 r also delays the onset of inclusion body formation as visualized via live imaging. ApiCCT1 r reduces mHtt-mediated toxicity in immortalized striatal cells derived from full-length knock-in HD mice, suggesting that therapeutic benefit may extend beyond effects on aggregation. These studies provide the basis for a potentially robust and unique therapeutic strategy to target mHtt-mediated protein pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes

Sontag

Joachimiak

Tan

et al. 2013

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

View full text Add to dashboard Cite

show abstract

“…Extracellular deposition of abnormal TTR (transthyretin) protein has been shown to cause familial amyloid polyneuropathy, and secreted PARK7 has been shown to degrade aggregated TTR to protect against the onset of amyloid polyneuropathy [26]. And with respect to PD, PARK7 has been detected in the cerebrospinal fluid of patients suffering from PD [28,29], and it has been found that administration of recombinant PARK7 into the brain of 6-OHDA-induced PD rat model improved PD phenotype [60], suggesting that extracellular PARK7 might exert a protective role against PD. There is a possibility that secreted PARK7 may protect neighboring cells from oxidative stress by means of a process similar to paracrine signaling, which possibility is thought to be supported by reports that PARK7 knockout astrocytes show inferior ability to protect neuronal cells against 6-OHDA-induced cell death both by co-culture and through astrocytes conditioned medium [61].…”

Section: Discussionmentioning

confidence: 99%

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

et al. 2018

View full text Add to dashboard Cite

PARK7/DJ-1 is a Parkinson disease- and cancer-associated protein that functions as a multifunctional protein involved in gene transcription regulation and anti-oxidative defense. Although PARK7 lacks the secretory signal sequence, it is secreted and plays important physiological and pathophysiological roles. Whereas secretory proteins that lack the endoplasmic reticulum-targeting signal sequence are secreted from cells by way of what is called the unconventional secretion mechanism, the specific processes responsible for causing PARK7 to be secreted across the plasma membrane have remained unclear. In the present study, we found that PARK7 secretion was increased by treatment with 6-OHDA via the unconventional secretory pathway in human neuroblastoma SH-SY5Y cells and MEF cells. We also found that 6-OHDA-induced PARK7 secretion was suppressed in Atg5-, Atg9-, or Atg16l1-deficient MEF cells or ATG16L1 knockdown SH-SY5Y cells, indicating that the autophagy-based unconventional secretory pathway is involved in PARK7 secretion. We moreover observed that 6-OHDA-derived electrophilic quinone induced oxidative stress as indicated by a decrease in glutathione levels, and that this was suppressed by pretreatment with antioxidant NAC. We further found that NAC treatment suppressed autophagy and PARK7 secretion. We also observed that 6-OHDA-induced autophagy was associated with activation of AMPK and ULK1 via a pathway which was independent of MTOR. Collectively these results suggest that electrophilic 6-OHDA quinone enhances oxidative stress, and that this is followed by AMPK-ULK1 pathway activation and induction of secretory autophagy to produce unconventional secretion of PARK7.Abbreviations: 6-OHDA: 6-hydroxydopamine; AMPK: AMP-activated protein kinase; ATG: autophagy related; CAV1: caveolin 1; ER: endoplasmic reticulum; FN1: fibronectin 1; GSH: glutathione; IDE: insulin degrading enzyme; IL: interleukin; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PARK7/DJ-1: Parkinsonism associated deglycase; PD: Parkinson disease; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; RPN1: ribophorin I; ROS: reactive oxygen species; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type

show abstract

“…ROS is an important mediator of neuronal cell death in PD. In addition, over-expression of DJ-1 leads to increased resistance to dopamine toxicity and reduced intracellular ROS (Inden et al, 2006;Junn et al, 2009;Kim et al, 2005). Thus, we examined the viability of cells with transduced Tat-DJ-1 proteins after the administration of 6-hydroxydopmine (6-OHDA), which is a toxin derived from dopamine.…”

Section: Discussionmentioning

confidence: 99%

Transduced Tat-DJ-1 Protein Protects against Oxidative Stress-Induced SH-SY5Y Cell Death and Parkinson Disease in a Mouse Model

Jeong

Kim

Woo

et al. 2012

Molecules and Cells

View full text Add to dashboard Cite

Parkinson's disease (PD) is a well known neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compact (SN). Although the exact mechanism remains unclear, oxidative stress plays a critical role in the pathogenesis of PD. DJ-1 is a multifunctional protein, a potent antioxidant and chaperone, the loss of function of which is linked to the autosomal recessive early onset of PD. Therefore, we investigated the protective effects of DJ-1 protein against SH-SY5Y cells and in a PD mouse model using a cell permeable Tat-DJ-1 protein. Tat-DJ-1 protein rapidly transduced into the cells and showed a protective effect on 6-hydroxydopamine (6-OHDA)-induced neuronal cell death by reducing the reactive oxygen species (ROS). In addition, we found that Tat-DJ-1 protein protects against dopaminergic neuronal cell death in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-induced PD mouse models. These results suggest that Tat-DJ-1 protein provides a potential therapeutic strategy for against ROS related human diseases including PD.

show abstract

PARK7 DJ-1 protects against degeneration of nigral dopaminergic neurons in Parkinson’s disease rat model

Cited by 165 publications

References 63 publications

Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes

Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

Transduced Tat-DJ-1 Protein Protects against Oxidative Stress-Induced SH-SY5Y Cell Death and Parkinson Disease in a Mouse Model

Contact Info

Product

Resources

About