The molecular mechanism of dopamine-induced apoptosis: identification and characterization of genes that mediate dopamine toxicity

Barzilai, Ari; Zilkha‐Falb, Rina; Daily, Dvora; Stern, Naftali; Offen, Daniel; Ziv, Ilan; Melamed, Eldad; Shirvan, Anat

doi:10.1007/978-3-7091-6301-6_4

Cited by 37 publications

(39 citation statements)

References 66 publications

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“…Similar events occur when primary mesencephalic dopaminergic neurons and rat pheochromocytoma PC12 cells are treated with 6-hydroxydopamine [Walkinshaw and Waters, 1995;Lotharius et al, 1999]. In these models of apoptotic cell death, several genes are involved, including Bcl2, BclX, cyclin B and p53 [Cassarino et al, 1997;Blum et al, 1997;Shirvan et al, 1997;Daily et al, 1999;Lotharius et al, 1999;Barzilai et al, 2000;Rabinovic et al, 2000]. Involvement of p53 in dopamine-induced cell death is in agreement with the involvement of p53 in regulating cell growth, apoptosis and cancer [Oren, 1999].…”

Section: Dopamine Induces Phenotypicsupporting

confidence: 55%

“…Dopamine can induce cell cycle arrest, intranucleosomal DNA fragmentation and apoptosis in cultures of chicken sympathetic neurons [Ziv et al, 1994;Barzilai et al, 2000] and human neuronal cell lines Junn and Mouradian, 2001]. Similar events occur when primary mesencephalic dopaminergic neurons and rat pheochromocytoma PC12 cells are treated with 6-hydroxydopamine [Walkinshaw and Waters, 1995;Lotharius et al, 1999].…”

Section: Dopamine Induces Phenotypicmentioning

confidence: 85%

“…Besides being able to induce programmed cell death at high doses (100-300 ÌM) [Ziv et al, 1994;Barzilai et al, 2000;Junn and Mouradian, 2001], herein we demonstrate that dopamine, at low, nonneurotoxic doses (20-50 ÌM) can decrease cell proliferation and induce characteristics compatible with differentiated neurons. These characteristics of differentiation include altered cell morphology, development of processes and increased 3 H-dopamine uptake.…”

Section: Discussionmentioning

confidence: 97%

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Dopamine Induces Phenotypic Differentiation or Apoptosis in a Dose-Dependent Fashion: Involvement of the Dopamine Transporter and p53

Porat

Arumugam

Simantov³

2001

Dev Neurosci

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The effect of dopamine on the growth, phenotypes (morphological and biochemical) and programmed cell death (apoptosis) of the human neuronal NMB cell line was examined. Exposure to 20–50 µM of dopamine decreased cell growth, induced an apparent differentiated cell morphology and increased ³H-dopamine uptake. At higher concentrations (100–300 µM) dopamine was neurotoxic and induced apoptosis, as reported previously. The observed effects of both low and high doses of dopamine were blocked by cocaine, which suggested involvement of dopamine transporters. Indeed, several experiments demonstrated the relationship between dopamine uptake of cells and their vulnerability to the toxic effect of dopamine. High concentrations of dopamine, which induced apoptosis, also increased p53 levels, detected by RT-PCR analysis and immunoblotting, whereas lower dopamine concentrations, which induced a differentiated phenotype, did not increase p53 immunoblotting. Dibutyryl-cAMP and dimethyl sulfoxide, which induced differentiation but not apoptosis of the NMB cells, did not increase p53 expression. These findings provide an insight into the role of dopamine, dopamine transporters and p53 in the differentiation and apoptosis of dopaminergic neurons, which will further our understanding of neuronal development and neurodegenerative diseases.

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Section: Dopamine Induces Phenotypicsupporting

confidence: 55%

Section: Dopamine Induces Phenotypicmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 97%

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Dopamine Induces Phenotypic Differentiation or Apoptosis in a Dose-Dependent Fashion: Involvement of the Dopamine Transporter and p53

Porat

Arumugam

Simantov³

2001

Dev Neurosci

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“…In addition, we identified three novel putative biomarkers, Trans elongation factor 1 (eEF1) and the collapsin response mediator proteins (CRMP-1 and -2) using protein libraries . Our observation of increases in CRMP-1 and CRMP-2 is in agreement with previous molecular data (Barzilai et al, 2000). In Alzheimer's disease (AD), CRMP-2 has been implicated in neurite degeneration, acting on the assembly and polymerization of microtubules (Gu et al, 2000).…”

Section: Vertebrate Brain Studies With Maldi Msisupporting

confidence: 93%

Molecular MALDI imaging: An emerging technology for neuroscience studies

Wisztorski

Croix

Macagno

et al. 2008

Developmental Neurobiology

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Mass spectrometry (MS) has become an essential tool for the detection, identification, and characterization of the molecular components of biological processes, such as those responsible for the dynamic properties of the nervous system. Generally, the application of these powerful techniques requires the destruction of the specimen under study, but recent technological advances have made it possible to apply the matrix-assisted laser desorption/ionization (MALDI) MS technique directly to tissue sections. The major advantage of direct MALDI analysis is that it enables the acquisition of local molecular expression profiles, while maintaining the topographic integrity of the tissue and avoiding time-consuming extraction, purification, and separation steps, which have the potential for introducing artifacts. With automation and the ability to display complex spectral data using imaging software, it is now possible to create multiple 2D maps of selected biomolecules in register with tissue sections, a method now known as MALDI Imaging, or MSI (for Mass Spectrometry Imaging). This creates, for example, an opportunity to correlate functional states, determined a priori with live recording or imaging, with the corresponding molecular maps obtained at the time the tissue is frozen and analyzed with MSI. We review the increasing application of MALDI Imaging to the analysis of molecular distributions of proteins and peptides in nervous tissues of both vertebrates and invertebrates, focusing in particular on recent studies of neurodegenerative diseases and early efforts to implement assays of neuronal development.

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“…First of all, higher tissue dopamine content is associated with increased cellular oxidative stress (53)(54)(55)(56)(57)(58). Second, higher DAT function could confer vulnerability to neural toxins in the environment.…”

Section: Dj-1 Null Mice Did Not Show Loss Of Sn Dopamine Neurons or Omentioning

confidence: 99%

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

Chen

Cagniard

Mathews

et al. 2005

Journal of Biological Chemistry

237

171

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Mutations in the DJ-1 gene were recently identified in an autosomal recessive form of early-onset familial Parkinson disease. Structural biology, biochemistry, and cell biology studies have suggested potential functions of DJ-1 in oxidative stress, protein folding, and degradation pathways. However, animal models are needed to determine whether and how loss of DJ-1 function leads to Parkinson disease. We have generated DJ-1 null mice with a mutation that resembles the large deletion mutation reported in patients. Our behavioral analyses indicated that DJ-1 deficiency led to age-dependent and taskdependent motoric behavioral deficits that are detectable by 5 months of age. Unbiased stereological studies did not find obvious dopamine neuron loss in 6-month-and 11-month-old mice. Neurochemical examination revealed significant changes in striatal dopaminergic function consisting of increased dopamine reuptake rates and elevated tissue dopamine content. These data represent the in vivo evidence that loss of DJ-1 function alters nigrostriatal dopaminergic function and produces motor deficits.Mutations in DJ-1 were recently identified in an autosomal recessive form of early-onset familial Parkinson disease (PD) 1 (1). The first reported mutation involves one large deletion of the first 5 exons and part of the promoter and another mutation was a missense mutation (L166P) that might cause instability of the DJ-1 protein by preventing it from folding properly and forming homodimers (2-5). Since this first report, a number of other mutations of DJ-1 including deletion mutations, point mutations, and a frameshift mutation have been found to cause PD (6 -10). These studies suggest that the loss of the normal function of DJ-1 leads to PD.However, the nature of the normal function of DJ-1 and the mechanism by which DJ-1 deficiency leads to PD are not well established. Studies prior to the report of its association with PD suggested that DJ-1 might play a role in oncogenesis (11), male fertility (12, 13), control of protein-RNA interaction (14), and in modulating androgen receptor transcription activity (15,16). In addition, the DJ-1 protein was shown to be responsive to oxidation (17, 18), suggesting a potential role in oxidative stress, a process often implicated in PD. Studies on PD-linked DJ-1 mutations indicate that wild-type, but not mutant, DJ-1 protects cells from oxidative stress (19 -21). Canet-Aviles et al. (22) reported that oxidation of the Cys 106 residue in DJ-1 could lead to its relocalization in mitochondria and protect cells from mitochondrial damage. Structurally, DJ-1 closely resembles the members of the ThiJ/PfpI family that have protease and chaperone activities (23-27). Recent biochemical studies suggested that DJ-1 might have protease (5) and redox-dependent chaperone activities (28). Therefore, putative functions of DJ-1 seem to converge on the common pathogenesis of PD implicated in other genetic and sporadic forms of PD.Despite those new insights into the biochemical and cellular functions of DJ-1, th...

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The molecular mechanism of dopamine-induced apoptosis: identification and characterization of genes that mediate dopamine toxicity

Cited by 37 publications

References 66 publications

Dopamine Induces Phenotypic Differentiation or Apoptosis in a Dose-Dependent Fashion: Involvement of the Dopamine Transporter and p53

Dopamine Induces Phenotypic Differentiation or Apoptosis in a Dose-Dependent Fashion: Involvement of the Dopamine Transporter and p53

Molecular MALDI imaging: An emerging technology for neuroscience studies

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

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