Respiratory chain enzyme activities in lymphocytes from untreated patients with Parkinson disease

Barroso, Natalia; Campos, Yolanda; Huertas, Rosa; Esteban, Jesús; Molina, J. A.; Alonso, A.; Gutiérrez-Rivas, Eduardo; Arenas, Joaquı́n

doi:10.1093/clinchem/39.4.667

Cited by 81 publications

(33 citation statements)

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“…This biochemical defect is the same as that produced in animal models of parkinsonism by MPTP and adds further support to the proposition that PD may be due to an environmental toxin with action(s) similar to those of MPTP.'' Further studies confirmed mitochondrial abnormalities in the periphery using platelet-rich preparations from another cohort of patients (Krige et al, 1992;Schapira et al, 1992) or blood lymphocytes (Barroso et al, 1993). Authors concluded that: ''our study supports the hypothesis that a biochemical defect in the respiratory chain may be involved in the pathogenesis of PD.''…”

Section: Influence Of Pesticides and Related Environmental Toxics In supporting

confidence: 78%

Microbiota and Other Preventive Strategies and Non-genetic Risk Factors in Parkinson’s Disease

Franco

Rivas‐Santisteban

Reyes‐Resina

et al. 2020

Front. Aging Neurosci.

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The exact cause of Parkinson's disease (PD), the second most prevalent neurodegenerative disease in modern societies, is still unknown. Many scientists point out that PD is caused by a complex interaction between different factors. Although the main risk factor is age, there are other influences, genetic and environmental, that individually or in combination may trigger neurodegenerative changes leading to PD. Nowadays, research remains focused on better understanding which environmental factors are related to the risk of developing PD and why. In line with the knowledge on evidence on exposures that prevent/delay PD onset or that impact on disease progression, the aims of this review were: (i) to comment on the non-genetic risk factors that mainly affect idiopathic PD; and (ii) to comment on seemingly reliable preventive interventions. We discuss both environmental factors that may affect the central nervous system (CNS) or the intestinal tract, and the likely mechanisms underlying noxious or protective actions. Knowledge on risk, protective factors, and mechanisms may help to envisage why nigral dopaminergic neurons are so vulnerable in PD and, eventually, to design new strategies for PD prevention and/or anti-PD therapy. This article reviews the variety of the known and suspected environmental factors, such as lifestyle, gut microbiota or pesticide exposition, and distinguishes between those that are harmful or beneficial for the PD acquisition or progression. In fact, the review covers one of the most novel players in the whole picture, and we address the role of microbiota on keeping a healthy CNS and/or on preventing the "side-effects" related to aging.

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Section: Influence Of Pesticides and Related Environmental Toxics In supporting

confidence: 78%

Microbiota and Other Preventive Strategies and Non-genetic Risk Factors in Parkinson’s Disease

Franco

Rivas‐Santisteban

Reyes‐Resina

et al. 2020

Front. Aging Neurosci.

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“…Such a scenario would align with the findings of this study. In support of this, numerous studies on mitochondrial respiration in various cell types in small cohorts of ante-mortem PD patients have failed to produce conclusive findings (Ambrosi et al, 2014;Barroso et al, 1993;Bravi et al, 1992;Cronin-Furman et al, 2013;Esteves et al, 2010;Martin et al, 1996;Parker and Swerdlow, 1998;Shinde and Pasupathy, 2006;Yoshino et al, 1992). Importantly, recently, a larger study examining mitochondrial respiration in immortalized lymphocytes from 30 patients found enhanced respiratory activity with no functional deficit (Annesley et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Misfolded α-synuclein causes hyperactive respiration without functional deficit in live neuroblastoma cells

Ugalde

Annesley

Gordon

et al. 2020

Disease Models &Amp; Mechanisms

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The misfolding and aggregation of the largely disordered protein, α-synuclein, is a central pathogenic event that occurs in the synucleinopathies, a group of neurodegenerative disorders that includes Parkinson's disease. While there is a clear link between protein misfolding and neuronal vulnerability, the precise pathogenic mechanisms employed by disease-associated α-synuclein are unresolved. Here, we studied the pathogenicity of misfolded α-synuclein produced using the protein misfolding cyclic amplification (PMCA) assay. To do this, previous published methods were adapted to allow PMCA-induced protein fibrillization to occur under non-toxic conditions. Insight into potential intracellular targets of misfolded α-synuclein was obtained using an unbiased lipid screen of 15 biologically relevant lipids that identified cardiolipin (CA) as a potential binding partner for PMCA-generated misfolded α-synuclein. To investigate whether such an interaction can impact the properties of α-synuclein misfolding, protein fibrillization was carried out in the presence of the lipid. We show that CA both accelerates the rate of α-synuclein fibrillization and produces species that harbour enhanced resistance to proteolysis. Because CA is virtually exclusively expressed in the inner mitochondrial membrane, we then assessed the ability of these misfolded species to alter mitochondrial respiration in live nontransgenic SH-SY5Y neuroblastoma cells. Extensive analysis revealed that misfolded α-synuclein causes hyperactive mitochondrial respiration without causing any functional deficit. These data give strong support for the mitochondrion as a target for misfolded α-synuclein and reveal persistent, hyperactive respiration as a potential upstream pathogenic event associated with the synucleinopathies. This article has an associated First Person interview with the first author of the paper.

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“…D1 and D2) and N-methyltransferase related to PD pathogenesis in lymphocytes from PD patients (Barbanti et al, 1999). In addition, impaired respiratory chain enzyme activities were detected in lymphocytes of PD patients, suggesting mitochondrial dysfunction in these cells (Barroso et al, 1993;Maruyama et al, 2000). Increased risk of apoptosis was also reported (Blandini et al, 2004;Calopa et al, 2010;Del Rio et al, 2004).…”

Section: The Activation Of Lymphocytes In Pdmentioning

confidence: 94%

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

Choi¹,

Polcher²,

Joas³

2016

EFSA Supporting Publications

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This report presents the outcomes of a systematic review (SR) identifying the mechanisms and chemicals involved in the pathogenesis of Parkinson's disease (PD) and childhood leukaemia (CL). This work serves as a basis for defining and mapping the causal linkages between a molecular initiating event (MIE) and a final adverse outcome (AO) that are relevant for the development of a prototype adverse outcome pathway (AOP) for assessing risk factors for PD and CL. Search for literature from 1990 to present was conducted using Web of Science, PubMed and TOXNET, and relevant references were selected using established inclusion/exclusion criteria and ranked using a set of quality control factors.For PD, 7,384 individual references were identified to be relevant for PD pathogenesis and chemicals associated with PD. Dopaminergic neurodegeneration in the substantia nigra leading to locomotor deficits was identified as the AO in PD. Other identified key events in PD pathogenesis include mitochondrial dysfunction, cellular accumulation of alpha-synuclein and oxidative stress. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone and paraquat are some chemicals identified to be associated with PD pathogenesis.For CL, 1,988 individual references were identified to be relevant for CL pathogenesis and chemicals associated with CL. Chromosomal translocation, genetic damage/mutation and hyperdiploidy are considered as driving forces of CL. Except for infant leukaemia, CL pathogenesis requires a 'two-hit' model with an initiating event occurring in utero followed by a secondary hit potentially occurring after birth. Potential MIEs leading to these driving mechanisms include aberrant DNA topoisomerase II activity and erroneous DNA repair. Epigenetics appears to also play an influential role in CL pathogenesis. Benzene, bioflavonoids and organophosphates are some chemicals identified to be implicated in CL pathogenesis.The challenges of developing AOPs for these two diseases and the data gaps identified from the outcomes of this SR are also elaborated in this report. The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. KEY WORDSSystematic Review, Parkinson Disease, Childhood Leukaemia, Pathogenesis, Chemicals, Pesticides, Adverse Outcome Pathway SUMMARYThe aim of this project was to perform a systematic review (SR) to collect relevant publications related to the mechanisms involved in the pathogenesis of Parkinson's disease (PD)...

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Respiratory chain enzyme activities in lymphocytes from untreated patients with Parkinson disease

Cited by 81 publications

References 0 publications

Microbiota and Other Preventive Strategies and Non-genetic Risk Factors in Parkinson’s Disease

Microbiota and Other Preventive Strategies and Non-genetic Risk Factors in Parkinson’s Disease

Misfolded α-synuclein causes hyperactive respiration without functional deficit in live neuroblastoma cells

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

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