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Relationship: 906

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Neuroinflammation leads to Degeneration of dopaminergic neurons of the nigrostriatal pathway

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Neuroinflammation
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Degeneration of dopaminergic neurons of the nigrostriatal pathway

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits adjacent Moderate Moderate Cataia Ives (send email) Open for citation & comment WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Cells of the innate (microglia and astrocytes) and adaptive (infiltrating monocytes and lymphocytes) immune system of the brain have, like other immune cells (in peripheral tissues), various ways to kill neighboring cells. This is in part due to evolutionary-conserved mechanisms evolved to kill virus-infected cells or tumor cells; in part it is a bystander phenomenon due to the release of mediators that should activate other cells and contribute to the killing of invading microorganisms. An exaggerated or unbalanced activation of immune cells can thus lead to parenchymal (neuronal) cell death (Gehrmann et al., 1995). Mediators known to have such effects, and that are also known to be produced during inflammation in the brain comprise components of the complement system and cytokines/death receptor ligands triggering programmed cell death (Dong and Benveniste, 2001). Besides these specific signals, various secreted proteases (e.g. matrix metalloproteases), lipid mediators (e.g. ceramide or gangliosides) or reactive oxygen species can contribute to bystander death of neurons (Chao et al., 1995; Nakajima et al., 2002; Brown and Bal-Price, 2003; Kraft and Harry, 2011; Taetzsch and Block, 2013). Especially the equimolar production of superoxide and NO from glial cells can lead to high steady state levels of peroxynitrite, which is a very potent cytotoxicant (Yuste et al., 2015). Already damaged neurons, with an impaired anti-oxidant defence system, are more sensitive to such mediators. An important role of microglia in the brain is the removal of cell debris (Xu et al., 2015). Healthy cells continuously display anti-“eat me” signals, while damaged and stressed neurons/neurites display “eat-me” signals that may be recognbized by microglia as signal to start phagocytosis (Neher et al., 2012), thus accelerating the loss of DA neurites in the striatum. Activated microglia surrounding DAergic neurons in PD express the M1 neurodegenerative phenotype (Hunot et al., 1999), which promote proliferation and function of CD4+ T cells (for review Appel et al., 2010), which in turn induce DA neuron toxicity, as assessed by experiments with immunodeficient mice (Brochard et al., 2009). Possible infiltration of other myeloid cells, such as monocytes or macrophages through a compromised blood-brain barrier, may also be involved in phagocytosis and neurodegeneration (Depboylu et al., 2012 ; Pey et al., 2014).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

• Mice deficient in microglia (depletion by a ganciclovir-thymidine kinase system under the CD11b promoter) were still susceptible to MPTP toxicity, while mixed cell cultures prepared from these deficient mice showed partial protection (Kinugawa et al., 2013).

• Although some publications show strong protection by COX-2 inhibition/deletion, others showed that mice deficient for COX-2 were partly protected against MPTP-induced decrease of DAergic neurons in substantia nigra, but not against DA terminal loss in striatum (Feng et al., 2000).

• Mice deficient in IL6 (IL6-/-) showed an increased vulnerability of the nigrostriatal pathway following MPTP treatment associated to a normal astrogliosis but a transient microgliosis, suggesting that transient microgliosis and IL6 may have also protective effects (Cardenas and Bolin, 2003).

• MMTV integration site 1 (Wnt 1) is a key transcript involved in DAergic neurodevelopment, and is dynamically regulated during MPTP-induced DA degeneration and glial activation. MPTP-activated astrocytes of the ventral midbrain were identified as candidate source of Wnt 1 by in situ hybridization and RT-PCR in vitro, suggesting that reactive astrocytes may be rather involved in neuroprotective/neurorescue pathways, as further demonstrated by deletion of Wnt 1 or pharmacological activation of Wnt/-catenin signaling pathway (L’Episcopo et al, 2011).

• The role of microglia, NADPH-oxidase and oxidative stress in paraquat-induced neurodegeneration is well established. Nevertheless, the mechanism connecting these three elements remain poorly understood since direct evidence for extracellular and/or intracellular formation of radical paraquat and superoxide is controversial.

• Rotenone (1-3 nM) applied directly on BV2 microglial cells increased their phagocytosis and the release of pro-inflammatory cytokines (TNF-alpha, IL-1 beta), suggesting that microglial cell can also be a primary target of rotenone (Zhang et al., 2014). However, these results in a transformed microglial cell line contrast with the experiments performed on isolated primary microglial cells, where rotenone (10-50 nM) was not able to trigger a direct activation (Klintworth et al., 2009).

• The regulation of inducible nitric oxide synthase (for production of peroxynitrite) differs strongly between rodents and human, and thus, the role of NO in human remains unclear (Ganster et al., 2001).

• While in human long-term use of anti-inflammatory drugs (NSAIDs, aspirin, iboprufen) for preventing PD onset or for slowing the progression is still controversial, a new strategy is emerging aiming at targeting microglial cells by modulating their activity, rather than simply trying to counteract their inflammatory neurotoxicity. The advantage of this therapeutic approach could be to reduce neuroinflammation and neurotoxicity, while at the same time strengthening intrinsic neuroprotective properties (Pena-Altamira et al., 2015)

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Rodent models have been mainly used to study the impact of neuroinflammation on DAergic nigrostriatal pathway degeneration, without any sex restriction. Neuroinflammation preceding neuronal death was detected in monkeys exposed to MPTP (Barcia et al., 2011); and in human, neuroinflammation is considered as an early event in the disease process (Innaccone et al., 2012).