Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders

Ben‐Shachar, Dorit; Zuk, R.; Gazawi, Haifa; Ljubuncić, P

doi:10.1016/j.bcp.2004.02.015

Cited by 111 publications

(68 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…DA-induced toxicity was initiated by the interaction with mitochondrial oxidative phosphorylation system causing inhibition of Complex I and decreasing ATP (Fig. 3A) [69]. In vitro studies demonstrated that the application of DA induces death of striatal cells [70].…”

Section: Dopamine and Dopamine Receptors In Neurotoxicitymentioning

confidence: 99%

“…Indeed, normal enzymatic metabolism of DA induces the formation of hydrogen peroxide via monoamine oxidase activity [74]. It has been shown that DA oxidized metabolites inhibit the mitochondrial respiratory system by the inhibition of complex I and reduction of ATP causing energy crisis [69]. In fact neurotoxins used to experimentally model nigral degeneration in vitro as well as in vivo such as 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cause neurodegeneration mediated by both ROS and mitochondrial inhibition (Fig.…”

Section: Oxidative Stressmentioning

confidence: 99%

Dopamine Receptors and Neurodegeneration

Rangel‐Barajas¹,

Coronel²,

Florán³

2015

Aging and disease

191

View full text Add to dashboard Cite

Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson's disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases.

show abstract

“…This was demonstrated at the level of mitochondrial function, mitochondrial respiration and complex I activity and at the level of gene and protein expression. The disease also exhibits an abnormal interaction between dopamine and the mitochondria 95,97 . Alterations in prohibitin were hypothesized to be involved in disturbed synaptic plasticity 98 .…”

Section: Disturbed Energy Metabolism: Evidence From Transcriptome Stumentioning

confidence: 99%

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia

Schmitt

Reich‐Erkelenz²,

Gebicke‐Härter

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

View full text Add to dashboard Cite

Schizophrenia is a severe neurobiological disease with genetic and environmental factors playing a role in the pathophysiology. Several brain regions have been implicated in the disease process and are connected in complex neuronal circuits. On the cellular and molecular level, affected connectivity between these regions, involving dysfunctional myelination of neuronal axons, as well as alterations on the synaptic level and energy metabolism of neurons leading to disturbances in synaptic plasticity are major findings in post-mortem studies. Microarray studies investigating genome-wide gene expression have contributed to the findings of alterations in complex pathways in relevant brain regions in schizophrenia. Moreover, first laser-capture microdissection studies allowed the investigation of gene expression in specific groups of neurons. However, it must be kept in mind that in post-mortem studies confounding effects of medication, mRNA quality as well as the capability of the brain for neuroplastic regenerative mechanisms in individuals with a lifetime history of schizophrenia may influence the complex pattern of alterations on the molecular level. Despite these limitations, hypothesis-free transcriptome studies in brain tissue from schizophrenia patients offer a unique possibility to learn more about underlying mechanisms, leading to new insights in the pathophysiology of the disease. A, et al. / Rev Psiq Clín. 2013;40(1):10-5 Keywords: Schizophrenia, gene expression, microarray, RT-PCR, in situ hybridization, brain regions. Schmitt ResumoEsquizofrenia é uma severa doença neurobiológica com fatores genéticos e ambientais desempenhando um papel na fisiopatologia. Diversas regiões cerebrais têm sido implicadas no processo da doença e estão conectadas em complexos circuitos neuronais. Nos níveis molecular e celular, a conectividade afetada entre essas regiões, envolvendo mielinização disfuncional dos axônios neuronais, bem como as alterações no nível sináptico e metabolismo energético levando a distúrbios na plasticidade sináptica, são os maiores achados em estudos post-mortem. Estudos de microarranjos investigando a expressão gênica contribuíram para os achados de alterações em vias complexas em regiões cerebrais relevantes na esquizofrenia. Além disso, estudos utilizando microdissecção e captura a laser permitiram a investigação da expressão gênica em grupos específicos de neurônios. Entretanto, deve ser mantido em mente que em estudos post-mortem, confusos efeitos de medicação, qualidade de RNAm, bem como capacidade de mecanismos regenerativos neuroplásticos do cérebro em indivíduos com história de vida de esquizofrenia, podem influenciar o complexo padrão de alterações no nível molecular. Apesar dessas limitações, estudos transcriptômicos livres de hipóteses em tecido cerebral de pacientes esquizofrênicos oferecem uma possibilidade única para aprender mais sobre os mecanismos subjacentes, levando a novas ópticas da fisiopatologia da doença. A, et al. / Rev Psiq Clín. 2013;40(1):10-5 Palavras-cha...

show abstract

Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders

Cited by 111 publications

References 73 publications

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

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

Dopamine Receptors and Neurodegeneration

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia

Contact Info

Product

Resources

About