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Relationship: 905


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

Impaired, Proteostasis 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
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 High Moderate Andrea Terron (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

One of the critical functions in the long-lived cells such as neurons is the clearing system for the removal of the unfolded proteins. This function is provided by two major systems, the Ubiquitin Proteosome System (UPS) and the Autophagy-Lysosome Pathway (ALP) (Tai HC et al. 2008; Korolchuck VI et al. 2010 and Ravikumar B et al. 2010). Impaired proteostasis with formation of misfolded α-synuclein aggregates deregulates microtubule assembly and stability with reduction in axonal transport and impairment of mithocondrial trafficking and energy supply (Esposito et al. 2007; Chen et al. 2007; Borland et al. 2008; O’Malley 2010; Fujita et al. 2014; Weihofen et al. 2009).

Pathological consequences of these deregulated process include interference with the function of synapses, formation of toxic aggregates of proteins, impaired energy metabolism and turnover of mitochondria and chronic endoplasmic reticulum stress; all eventually leading to degeneration of DA neurons in the nigrostriatal pathway (Fujita et al. 2010, Shulman et al. 2011, Dauer et al. 2003, Orimo et al.2008, Raff et al. 2005; Schwarz 2015).

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 Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The weight of evidence for the relationship between impaired proteostasis and degeneration of dopaminergic neurons of the nigrostriatal pathway is strong. The biological plausibility is based on the knowledge of the physiological cellular process governing the cleaning processes of degradated proteins and organells and on the observations done in genetic and idiopathic forms of Parkinson's disease. Dose and time concordance support a strong response-respose relationships which is also supported by the very well known chronic and progressive behviour of the Parkinson's disease. Although essentiality has been demonstrated in multiple models and lines of evidence, including knockout animals, a single molecular chain of events cannot be established; therefore essentiality for this KEs relationship was considered moderate.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The fact that impaired proteostasis can induce degeneration of DA neurons of the nigrostriatal pathway is well known and based on the understanding of the physiological cellular processes involved in removing degraded/misfolded proteins as they are critical for normal mitochondria and axonal transport. Accumulation of misfolded and/or aggregated α-synuclein and the presence of abnormal mitochondria is a consequence of deregulation of this clearing process, and the Lewy bodies, a pathological hallmark of sporadic PD, stain specifically for proteins associated with UPS (Fornai et al., 2003; Gai et al., 2000; McNaught et al., 2002).

Impaired proteostasis has been described in humans affected by sporadic PD (McNaught et al.; 2001, 2003), and changes induced by excess cellular levels of degraded proteins in nigral dopaminergic neurons cause a progressive decline in lysosome function, i.e. ALP system, contributing to neurodegeneration (Decressac et al. 2013). In this context, the ALP system is likely working in a complementary way, with the UPS being the major cleaning system in the soma and the ALP playing a role at pre-synaptic sites (Friedman et al., 2012). Pathological observations from patients affected by PD and from animal models show an increased number of autophagic vacuoles or autophagic markers (Alvarez-Erviti et al., 2010; Crews et al. 2010). Additional observations support the role of impaired proteostasis in nigrostriatal toxicity such as : several genetic variants of sporadic PD are due to susceptible genes able to participate in or modify proteostasis (Shulman et al. 201, Fornai et al. 2003, Shimura et al. 2000, Leroy et al.1998) and striatal microinfusion of proteasome inhibitors induce selective nigrostriatal toxicity with loss of DA and DA metabolites (DA, DOPAC and HVA) in the striatum, retrograde loss of nigral DA cell and intracytoplasmatic inclusions positive for protein of the UPS (Fornai et al. 2003).

Transgenic overexpression of mutant or wild-type forms of α-synuclein in mice causes neuropathological changes including dystrophic neurites and α-synuclein positive LB-inclusion (Dauer et al. 2003; Masiliah et al. 2000). However, they fail to reproduce specific cell death in the nigrostriatal pathway. In contrast, injection of human α-synuclein expressing viral vectors into the SN of adult rats causes a selective death of dopaminergic neurons and formation of LB inclusions (Dauer et al. 2003; Kirik et al. 2002; Lo Bianco et al. 2002). These effects were observed with adeno-associated virus –mediated expression of A30P α-synuclein and with lentiviral-mediated expression of α-synuclein in rats, mice and non-human primates (Shulman 2010; Kirk et al.2003; Klein et al. 2002; Lo Bianco et al. 2002 and 2004; Lauwerset al. 2003).

Impaired proteostasis and formation of proteins aggregates also affect the axonal transport and mitochondrial trafficking. α-synuclein mutants accumulate in the neuronal soma when overexpressed, reducing the axonal transport (Kim-Han et al. 2011; Saha et al.2004); in addition, overexpressed vesicle-associated α-synuclein binds to the microtubules with a detrimental role on axonal transport (Kim-Han et al. 2011; Yang et al. 2010). Postmortem studies on PD patients are indicative of axonal damage. It appears that axonal changes precede neuronal loss, supporting the idea that axonal impairments are early events in neurodegenerative disorders (Orimo et al. 2005 and 2008, Raff 2002, Braak et al. 2004). These changes, and observation from animals models using the chemical stressor MPTP (Meissner et al. 2003, Serra et al. 2002, Hasbani et al. 2006) are supporting the notion that DA neurons of the nigrostriatal pathway degenerate through a “dying back” axonopathy (Raff et al. 2002). It was demonstrated that axonal degeneration follows an active process distinct from cell body loss in a Wallerian degeneration slow (WldS) mutant mouse transgenic model. In this model, axonal degeneration in a variety of disorders is inhibited. In WldS mice, acute treatment with MPTP (20 mg/kg ip for 7 days) resulted in attenuated nigrostriatal axon degeneration, and attenuated DA loss, but cell bodies were not rescued (Hasbani et al. 2006). Indeed, multiple evidences from genetic and experimental models (particularly using MPTP as a chemical stressor) support an early and critical role of axonal impairment with early occurrence of Lewy neurites preceding Lewy bodies formation and cell death (O’Malley 2010).

In addition, a strong link between mitochondrial dysfunction and PD came from the discovery that mutations in PINK1, α-synuclein, LRRK2, parkin and DJ-1, all linked with genetic causes of PD, can affect mitochondrial function (Rappold et al.2014, O’Malley 2010). Deregulation of mitochondrial dynamics (fission, fusion and movement of mitochondria) can affect neuronal activity and viability and imbalance of mitochondrial dynamics have been reported in experimental models of PD with mutated α-synuclein (Tieu, 2014) or chronic model of primary neuronal cells treated with low concentrations (0.1-1 nM) of rotenone (Arnold et al. 2011). Progression of neuronal changes with formation of Lewy neurites and reduction of mitochondrial movement leading to cell death has been also observed in-vitro in a chronic cell-based model (SH-SY5Y neuroblastoma cell line) treated with Rotenone (50nM for 21 days). In this assay, reduction in mitochondrial movement was associated with a progressive damage, first including formation of Lewy neurites, followed by cell death (Borland et al.2008).

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
  • MPTP can induce damage to nigrostriatal neurons without formation of Lewy bodies (hall mark of PD). Acutely intoxicated humans and primates with MPTP lack LB-like formation (Dauer et al. 2003; Forno et al. 1986, 1993). Similarly, discontinuous administration of rotenone, even at high doses, damages the basal ganglia but produce no inclusions (Heikkila et al. 1985; Ferrante et al. 1997, Lapontine 2004). To reproduce the formation of neuronal inclusions, continuous infusion of MPTP or rotenone is necessary.
  • Acute intoxication with rotenone seems to spare dopaminergic neurons (Dauer et al 2003, Ferrante 1997). In addition, in rats chronically infused with rotenone showed a reduction in striatal DARPP-32-positive, cholinergic and NADPH diaphorase-positive neurons (Hoglinger et al. 2003) or in other brain regions. These results would suggest that Rotenone can induce a more widespread neurotoxicity (Aguilar et al. 2015).
  • The vulnerability of the dopaminergic pathway still remains circumstantial. The selectivity of MPP+ for dopaminergic neurons is due to its selective uptake via dopamine transporter (DAT), which terminates the synaptic actions of dopamine (Javitch et al. 1985, Pifl et al. 1993, Gainetdinov et al.1997, Hirata et al. 2008). Selectivity of rotenone for dopaminergic neurons is not fully understood (Hirata 2008).
  • Transgenic overexpression of α-synuclein induces neurotoxicity (ie neuronal atrophy, distrophic neuritis, astrocytosis and LB-like formation). However they fail to cause death of dopaminergic neurons. Nevertheless, injection of the human protein or mutated form expressing viral vectors into the SN, are able to induce all the pathological changes characteristic of PD. This discrepancy could be due to the higher expression of α-synuclein in the viral vector model or because in these models, α-synuclein overexpression would occur suddenly in adult animals (Dauer et al. 2003). In addition, transgenic expression of C-terminal truncated α-synuclein also leads to motor symptoms but neuronal degeneration is not reported (Halls et al. 2015).
  • There is conflicting literature on whether increased autophagy would be protective or enhances damage. Similarly, a conflicting literature exists on extent of inhibition or activation of different protein degradation system in PD and a clear threshold of onset is unknown (Fornai et al. 2005).
  • Several mechanisms may affect the axonal transport in neurons showing swelling of neurites positive for α-synuclein. These include e.g. ROS production, lysosome and mitochondria membranes depolarization, increased permeability and microtubule depolymerization (Kim-Ham et al.2011, Borland et al.2008, Choi et al.2008). As both MPTP and rotenone could directly trigger these effects, a clear mechanistic understanding leading to cell death is difficult to identify (Aguilar et al. 2015).
  • Different features of imbalanced proteostasis can trigger one another (e.g. disturbed protein degradation, pathological protein aggregation, microtubule dysfunction); and each of them can lead to cell death. Therefore, the “single” triggering event triggering axonal degeneration or neuronal death is not known. For instance, for α-synuclein aggregation, it is not clear whether this causes death because some vital function of neurons is lost, or whether some protein increases e.g. because of inhibited chaperone-mediate autophagy (Kaushik et al. 2008, Cuervo et al. 2014).
  • Real-time changes in DA axons are difficult to assess, accounting for the limitation of testing models of structural or trafficking impairment in-vivo.

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
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. 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

Multiple animal modeles have been used to mimic PD (Johnson et al. 2015). There are no sex restriction; however, susceptibility to MPTP increases with age in both non-human primates and mice (Rose et al.1993, Irwin et al. 1993, Ovadia et al. 1995).


List of the literature that was cited for this KER description. More help

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