Increased level of DJ-1 in the cerebrospinal fluids of sporadic Parkinson’s disease

Waragai, Masaaki; Wei, Jianshe; Fujita, Masayo; Nakai, Michikazu; Ho, Gilbert; Masliah, Eliezer; Akatsu, Hiroyasu; Yamada, Tatsuo; Hashimoto, Makoto

doi:10.1016/j.bbrc.2006.05.011

Cited by 174 publications

(111 citation statements)

References 34 publications

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“…Taken together, our findings indicate that terminal differentiation of ADAS cells into electrically mature neurons does not occur in vitro under the conditions tested. In this respect, our results are similar to those reported for multipotent skin-derived progenitor (SKP) cells which express neuro-glial markers but fail to progress from neuroblast to neuron-like stages in vitro (Fernandes, Kobayashi et al 2006), possibly due to lack of electrical stimulation (Waragai, Wei et al 2006) or other critical signaling cues which may be possible in vivo through interactions with endogenous cell populations.…”

Section: Adas Cell Cultures Do Not Display Spontaneous or Evoked Elecsupporting

confidence: 88%

Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease

McCoy

Martinez

Ruhn

et al. 2008

Experimental Neurology

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Adult adipose contains stromal progenitor cells with neurogenic potential. However, the stability of neuronal phenotypes adopted by Adipose-Derived Adult Stromal (ADAS) cells and whether terminal neuronal differentiation is required for their consideration as alternatives in cell replacement strategies to treat neurological disorders is largely unknown. We investigated whether in vitro neural induction of ADAS cells determined their ability to neuroprotect or restore function in a lesioned dopaminergic pathway. In vitro-expanded naïve or differentiated ADAS cells were autologously transplanted into substantia nigra 1-week after an intrastriatal 6-hydroxydopamine injection. Neurochemical and behavioral measures demonstrated neuroprotective effects of both ADAS grafts against 6-hydroxydopamine-induced dopaminergic neuron death, suggesting that pre-transplantation differentiation of the cells does not determine their ability to survive or neuroprotect in vivo. Therefore, we investigated whether equivalent protection by naïve and neurally-induced ADAS grafts resulted from robust in situ differentiation of both graft types into dopaminergic fates. Immunohistological analyses revealed that ADAS cells did not adopt dopaminergic cell fates in situ, consistent with the limited ability of these cells to undergo terminal differentiation into electrically active neurons in vitro. Moreover, re-exposure of neurally-differentiated ADAS cells to serum-containing medium in vitro confirmed ADAS cell phenotypic instability (plasticity). Lastly, given that gene expression analyses of in vitro-expanded ADAS cells revealed that both naïve and differentiated ADAS cells express potent dopaminergic survival factors, ADAS transplants may have exerted neuroprotective effects by production of trophic factors at the lesion site. ADAS cells may be ideal for ex vivo gene transfer therapies in Parkinson's disease treatment.

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Section: Adas Cell Cultures Do Not Display Spontaneous or Evoked Elecsupporting

confidence: 88%

Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease

McCoy

Martinez

Ruhn

et al. 2008

Experimental Neurology

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“…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%

“…Increase in PARK7 secretion into serum or plasma has been observed in patients with breast cancer, melanoma, stroke, familial amyloid polyneuropathy, and PD [21–27]. There have been conflicting reports of both increase [28] and decrease [29] in the amount of PARK7 in cerebrospinal fluid in sporadic PD patients as compared with control groups. Secreted PARK7 plays important physiological and pathophysiological roles which include involvement in anti-oxidative effects [30], extracellular signaling between neighboring neuronal cells [31], angiogenic and osteogenic factors [32], and degradation of aggregated protein [26].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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

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“…No differences were reported in serum DJ-1 levels measured in PD patients and healthy controls in a study performed by Maita et al, 86 whereas other studies performed in CSF or plasma reported higher DJ-1 levels in PD patients than controls. 87,88 Moreover, while upregulation of CSF DJ-1 levels in early stages of PD was more marked compared to levels observed in advanced stages and in controls, plasma DJ-1 levels appeared to be higher in advanced disease. Likewise, these studies revealed similar increases in PD and in neurological diseases with primary synucleinopathy.…”

Section: Genetic Markersmentioning

confidence: 94%

Biomarkers for Evaluation of Clinical Efficacy of Multipotential Neuroprotective Drugs for Alzheimer's and Parkinson's Diseases

et al. 2009

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Summary: During the last century, the world population has shown a staggering increase in its proportion of elderly members and thus neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), respectively, are becoming an increasing burden on society. Among the diverse, significant challenges facing clinicians, is the improvement of diagnostic measures to detect early and subtle symptoms, a phase in which prevention efforts might be expected to have their greatest impact and provide a measure of disease progression that can be evaluated during the course of drug treatment. At present, clinical diagnosis of AD and PD is based on a constellation of symptoms and manifestations, although the disease originated several years earlier. Given the multiple etiological nature of AD and PD, it is reasonable to assume that the initial causative pathobiological processes may differ between the affected individuals. Therefore, the availability of biological markers or biomarkers will help not only early disease diagnosis, but also delineate the pathological mechanisms more definitively and reliably than the traditional cognitive and neurological phenotypes. In the current article, we review the literature on biochemical, genetic, and neuroimaging biomarkers and discuss their predictive value as indicative for disease vulnerability to detect individuals at risk for PD and AD, and to determine the clinical efficacy of novel, disease-modifying (neuroprotective) strategies.

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Increased level of DJ-1 in the cerebrospinal fluids of sporadic Parkinson’s disease

Cited by 174 publications

References 34 publications

Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease

Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson's disease

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

Biomarkers for Evaluation of Clinical Efficacy of Multipotential Neuroprotective Drugs for Alzheimer's and Parkinson's Diseases

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