Relationship: 907



Degeneration of dopaminergic neurons of the nigrostriatal pathway leads to Neuroinflammation

Upstream event


Degeneration of dopaminergic neurons of the nigrostriatal pathway

Downstream event



Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits adjacent Moderate Moderate

Taxonomic Applicability


Sex Applicability


Life Stage Applicability


Key Event Relationship Description


Several chemokines and chemokines receptors (fraktalkine, CD200) control the neuron-microglia interactions and a loss of this control on the side of neurons can trigger microglial reactivity without any further positive signal required (Blank and Prinz, 2013; Chapman et al., 2000; Streit et al., 2001). Upon neuronal injury, signals termed “Damage-Associated Molecular Patterns (DAMPs)” are released by damaged neurons to promote microglial reactivity (Marin-Teva et al., 2011; Katsumoto et al., 2014). These are for instance detected by Toll-like receptors (TLRs) (for review, see Hayward and Lee, 2014). TLR-2 functions as a master sensing receptor to detect neuronal death and tissue damage in many different neurological conditions including nerve transection injury, traumatic brain injury and hippocampal excitotoxicity (Hayward and Lee, 2014). Astrocytes, the other cellular actor of neuroinflammation besides microglia (Ranshoff and Brown, 2012) are also able to sense tissue injury via e.g. TLR-3 (Farina et al., 2007; Rossi, 2015), and neuronal injury can result in astrocytic activation (Efremova, 2015).

The SNpc can be particularly vulnarable to the inflammatory process; its contains more microglia than astrocytes when compared with other areas of the brain and this can promote stronger neuroinfammation (Mena et al. 2008, Kim et al. 2000).

Evidence Supporting this KER


Biological Plausibility


Kreutzberg and coworkers (1995, 1996) showed that neuronal injury generally leads to activation of microglia and astrocytes. This is a general phenomenon: for instance it is always observed in ischemic damage (stroke; often in the form of glial activation following neuronal injury (Villa 2007)) as well as in stab or freeze injuries (Allahyari and Garcia, 2015). It is also observed regularly when neurons are killed by highly specific neurotoxicants that do not affect glia directly, such as injection of quinolinic acid or of 6-hydroxydopamine into the striatum (Hernandez-Baltazar et al., 2013; Arlicot et al., 2014). The vicious circle of neuronal injury triggering glial activation and glial activation triggering/enhancing neurodegeneration is often assumed to be a key element in the pathogenesis of neurodegenerative diseases, not just PD, but also Alzheimer's disease, prion disease and many others(Hirsch and Hunot, 2009; Tansey and Goldberg, 2009; Griffin et al., 1998; McGeer and Mc Geer, 1998; Blasko et al., 2004; Cacquevel et al., 2004; Rubio-Perez and Morillas-Ruiz, 2012; Thundyil and Lim, 2014; Barbeito et al., 2010).

Innate immune system, mainly microglia and astrocytes is primary involved in Parkinson's disease the(Lucin et al. 2009, Glass et al. 20101, Rocha et al. 2012), and neurons are knowns to actively regulate the microglia response to stress (Mott et al. 2004, Cardona et al. 2006). Presence of reactive microglia has been observed in post-mortem brain tissue from PD patients or in people following intoxication with MPTP as well as in animal models of PD (McGeer et al. 1988, Langston et al. 1999, McGeer et al. 2003, Czlonkowska et al. 1996, Walsh et al. 2011). In co-cultures of neurons and microglia neuronal damage/cell death triggers microglia activation that potentiates MPTP-induced neuronal injury (Gao et al. 2003).

Empirical Evidence




MPP+: The chemokine fractalkine (regulating neuron-glia interactions) was found to be released by neurons after unilateral injection of MPP+ in substantia nigra. It induced microglial activation by binding on the microglial receptor CXCR1 (Shan et al., 2011). Similarly, in chronically MPTP- injected macaques, metalloproteinases-9 (MMP-9) released by injured neurons favor glial activation (Annese et al., 2015). Advanced glycation endproducts (AGEs), which are endproducts of reactions involving ROS, colocalized with DAergic neurons 2 days post last MPTP injection, suggesting neuronal injury (Teismann et al., 2012). In contrast, the receptors for AGEs (RAGEs) were found on microglial cells and astrocytes (Teismann et al., 2012). RAGE can activate NF-kappaB, the transcription factor involved in the inflammatory response (Abdelsalam and Safar, 2015). Ablation of RAGE proved to be protective against MPTP-induced decreases of TH+ neurons, by decreasing NF-kappaB p65 nuclear translocation and by mitigating microglia and astrocyte reactivities (Teismann et al., 2012).

Rotenone: Rotenone-induced neurotoxicity was less pronounced in neuron-enriched cultures, than in neuron-glia co-cultures (Gao et al., 2002), sugggesting that neuron-glia interactions are critical for rotenone-induced neurodegeneration. Indeed, CD200-CD200R signaling regulates neuron-glia interactions and holds microglia in a quiescent state (Biber et al., 2007). Therefore, inhibition of CD200R by blocking antibodies increased rotenone-induced DA neurotoxicity in neuron-glia mesencephalic co-cultures (Wang et al., 2011). Aging is associated with a decrease of CD200 expression (Wang et al., 2011) and deficits in neuronal CD200 production is also observed in several animal models of Parkinson’s disease (Sung et al., 2012 ; Wang et al., 2011 ; Zhang et al., 2011). Inhibition of RAGE, which is upregulated in the striatum following rotenone exposure and in response to neuroinflammation, decreases rotenone-induced apoptosis by decreasing mitochondrial cytochrome c release and caspase-3 activation and suppresses NF-kappaB activation, as well as the downstream inflammatory markers TNF-alpha, i-NOS and myeloperoxidase (Abdelsalam and Safar, 2015), showing again intermingled links between neuronal injury/death and neuroinflammation.


Uncertainties and Inconsistencies


• Triggering of glia by injured neurons may not necessarily be due to the damage of neurons, but it may also be due to released synuclein (Sanchez-Guajardo, 2010)

• In a AAV alpha-synucleinoptahy model, it was shown that cytoskeletal perturbation and accumulation of alpha-synuclein were sufficient to induce microglial reactivity, suggesting that neuroinflammation appears early in the disease process and is not a result triggered by cell death (Chung et al., 2009)

• Direct effects of toxicants on glia cannot be completely excluded. They have been reported for most toxicants in one or the other publication (rotenone, paraquat, MPP+) (Zhang et al., 2014; Rappold et al., 2011; Brooks et al., 1989). The overwhelming evidence speaks against such effects for rotenone and MPP+ (Klintworth et al., 2009), but for paraquat there is evidence of direct interaction with microglial membrane NADPH oxidase (Rappold et al., 2011).

Quantitative Understanding of the Linkage


Some examples of quantitative relationships between KEup and KEdown are given below. For KEdown Neuroinflammation, only the features measured are cited, as neuroinflammation is a complex KE involving several cell types and measured by changes in the expression /release of several markers


KE upstream

Degeneration of DAergic nigrostriatal pathway

KE downstream








about 25 % decrease of TH+ neurons 24h-72h post-injection

Microglial and astroglial reactivities in substantia nigra and striatum

MPTP 20mg/kg i.p.

4 injections at 2h intervals

Annese et al., 2013

MMP-9 released by neurons as trigger of neuroinflammation

about 60% decrease of TH+ neurons in subt nigra and of DA terminals in striatum 7days post-injection

increase in ED1+ cells (macrophagic microglia or invading monocytes)


20 mg/kg i.p.

4 injections at 2h intervals

Chung et al., 2013

MMP-3-induced disruption of BBB

about 50% decrease of TH+ neurons

microglial and astroglial reactivity in substantia nigra and striatum

MPTP 30mg/kg i.p. each day during 5 days

Teisman et al., 2012

RAGE as trigger of neuroinfl.

about 50% decrease of DA content in striatum

increase of TNF-alpha (about 5X) and of i-NOS (about 8X) in striatum

Rotenone 1.5mg/kg s.c. for 21 days

Abdesalam and Safar, 2015



Response-response Relationship




Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability


Beside the rodent models, the concept of vicious circle with neuronal injury leading to neuroinflammation and neuroinflammation triggering or enhancing neurodegeneration is described in several neurodegenerative diseases in human, without any sex restriction (Hirsch and Hunot, 2009; Tansey and Goldberg, 2009; Griffin et al., 1998; McGeer and Mc Geer, 1998; Blasko et al., 2004; Cacquevel et al., 2004; Rubio-Perez and Morillas-Ruiz, 2012; Thundyil and Lim, 2014; Barbeito et al., 2010). Aging is an aggravating factor and increases the risk for developing a neurodegenerative disease (Kawas et al., 2000; Blasko et al., 2004).



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