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Relationship: 905

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Impaired, Proteostasis leads to Degeneration of dopaminergic neurons of the nigrostriatal pathway

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
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

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. 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 Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. 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
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   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
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  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.
Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized 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).

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Agiular JS, Kostrzewa RM. Neurotoxin mechanisms and processes relevant to parkinson’s disease: un update. Neurotox Res. DOI 10.1007/s12640-015-9519-y.

Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero JD, Ferrer I, Obeso JI, Schapira AHV. 2010. Chaperone-Mediated Autophagy Markers in Parkinson Disease Brains. Arch Neurol. 67(12). 1464-2.

Arnold, B., et al. (2011). "Integrating Multiple Aspects of Mitochondrial Dynamics in Neurons: Age-Related Differences and Dynamic Changes in a Chronic Rotenone Model." Neurobiology of Disease 41(1): 189-200.

Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. 2000. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nature neuroscience. 3 (12) 1301-6.

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Borland MK, Trimmer PA, Rubinstein JD, et al (2008). Chronic, low dose rotenone reproduces Lewy neuritis found in early stages of Parkinson’s disease, reduces nitochondrial movement and slowly kill differentiated SH-SY5Y neural cells. Mol Neurodegener 3-21.

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Choi WS, Kruse SE, Palmiter RD, Xia Z. 2008. Mitochondrial complexI inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat. PNAS. 105 (39) 15136-41.

Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, Hansen L, Adame A, Galasko D, Malsiah E. 2010. Selective molecular alterations in the autophagy pathway in patients with lewy body disease and in models of α-synucleinopathy. 5(2)1-16.

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Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Lewis VJ, Hersch S, Sulzer D, Przedborski S, burke R, Hen R. 2002. Resistance of α-synuclein null mice to the parkinsonian neurotoxicity MPTP. PNAS. (99) 14524-9.

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Hirata Y, Suzuno H, Tsuruta T, Oh-hashi K, Kiuchi K. 2008. The role of dopaminergic transporter in selective toxicity of manganese and rotenone.Toxicology.(244). 249-6.

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Kim-Han JS, Dorsey JA, O’Malley KL. 2011. The parkinsonian mimetic MPP+, specifically impairs mitochondrial transport in dopamine axons. The Journal of Neuroscience. 31(19) 7212-1.

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Klein RL, King MA, Hamby ME, Meyer EM. 2002. Dopaminergic cell loss induced by human A30P α-synuclein gene transfer to the rat substantia nigra. Hum.Gene.Ther. (13) 605-2.

Korolochuk VI, Menzies FM, Rubinsztein DC. 2010. Mechanism of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett. (584) 1393-8.

Inden M, Yoshihisa Kitamura, Hiroki Takeuchi, Takashi Yanagida, Kazuyuki Takata, Yuka Kobayashi, Takashi Taniguchi, Kanji Yoshimoto, Masahiko Kaneko, Yasunobu Okuma, Takahiro Taira, Hiroyoshi Ariga and Shun Shimohama. 2007. Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone. Journal of Neurochemistry. 101.(6).1491–4.

Irwin JK, 1993, Parkinson’s disease: Past, Present and Future. Neuropsycopharmacology. 9(1). 1-1. Langston JW, ballard P, Irwin I. 1983. Chronic parkinsonism in human due to a product of meperidine-analog synthesis. Science. (219) 979-0.

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