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Relationship: 910

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

Degeneration of dopaminergic neurons of the nigrostriatal pathway leads to Parkinsonian motor deficits

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Degeneration of dopaminergic neurons of the nigrostriatal pathway

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Parkinsonian motor deficits

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	High	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

Degeneration of dopaminergic (DA) neuron terminals in the striatum and the degeneration of DA neurons in the substantia nigra pars compacts (SNpc) are the defining histopathological events observed in idiopathic, familial, and toxicant-evoked cases of Parkinson’s Disease (PD) (Tolwani et al. 1999; Bove et al. 2012). The loss of nigrostriatal DA neurons leads to a decline in the levels of DA in the striatum (Koller et al. 1992). Striatal DA is involved in the modulation of extrapyramidal motor control circuits. A decline in striatal DA leads to an overactivation of the two principal basal ganglia output nuclei (GPi/STN). Therefore, the inhibitory GABAergic neurons that project to thalamo-cortical structures are overactivated and inhibit cortical pyramidal motor output performance. This inhibited output activity is responsible for key clinical symptoms of PD such as bradykinesia and rigor.

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

Motor abnormalities observed in PD display large interindividual variations.

The model of striatal DA loss and its influence on motor output ganglia does not allow to explain specific motor abnormalities observed in PD (e.g. resting tremor vs bradykinesia) (Obeso et al. 2000). Other neurotransmitters (Ach) may play additional roles.
There are some reports indicating that in subacute rotenone or MPTP models (non-human primates), a significant, sometimes complete, recovery of motor deficits can be observed after termination of toxicant treatment. While the transient loss of striatal DA can be explained by an excessive release of DA under acute toxicant treatment, the reported losses of TH-positive neurons in the SNpc and their corresponding nerve terminals in the striatum are currently not explained (Petroske et al. 2001).
In MPTP treated baboons, the ventral region of the pars compacta was observed to be more severely degenerated that the dorsal region. This pattern is similar to the degeneration pattern in idiopathic PD in humans. These observations indicate that two subpopulations of nigrostriatal DA neurons with different vulnerabilities might exist (Varastet et al. 1994).

According to the classical model of basal ganglia organization, DA is assumed to have a dichotomous effect on neurons belonging either to the direct or indirect pathway. More recent evidence however rather indicates that D1 and D2 receptors are expressed on most striatal neurons in parallel (Aizman et al. 2000).
Large variability exists regarding the onset of the downstream AO. This is dependent upon the the stressor used and the route of exposure and variability in the experimentl outcome consequent to differences in the route of exposure is a frequent inconsistencies.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

An example of quantitative analysis is reported in the table below. The analysis of the empirical data produced with the chemical toxicants supports a strong response- response relationship between the KE up and the KE down which also indicative of the temporal progression and relationship between the degeneration of striatal terminals of DA neurons, loss of DA neurons in the SNpc and the occurrence and severity of the motor deficits. This is also quantitatively supported by studies conducted in human PD patients.

Upstream key event (KE 4)	Downstream key event (AO)	References	Comments
Rat models
45 % loss of TH-positive SNpc neurons in 7 month old rats, ca. 40 % loss in 12 month old rats Striatal DA reduced from 90 ng/mg (control) down to 45 ng/mg TH pos. neuron number 18000 (control) 10000 (rotenone)	Bradykinesia, postural instability, rigidity observed in 50 % of cases: 3 month old rats: after 12 days of rotenone 7 + 12 month old rats. After 6 days of rotenone Postural instability test: Distance required for the animal to regain postural stability: 3.5 cm (control) 5 cm (rotenone) Rearing test (rears/ 5 min): 10 (control 3 (rotenone) Loss of rearing performance evoked by rotenone was reversed by the DA agonist Apomorphine in 3 month old rats	Cannon et al. 2009	Lewis rats + rotenone (3 mg/kg/day, i.p. daily)
Dopamine in the anterior and posterior striatum reduced by ca. 50 %.	Catalepsy test: decline from 35 s to 5 s. Grid test: decline from 30 s to 4 s Distance travelled in 10 min: reduction from 37 m to 17 m. Number of rearings: decline from 65 to 30. Inactivity time increased from 270 s to 400 s. Partial reversibility by L-DOPA treatment: L-DOPA: number of rearings increased from 16 to 30. L-DOPA: inactivity time reduced from 450 s to 360 s. L-DOPA: increase in the distance travelled from 12 to 16 m.	Alam et al. 2004	Rats + rotenone (2.5 mg/kg) daily over the course of 48 days.
TH staining intensity reduced from 0.2 to 0.12	Rearing scores reduced from 80 % (vehicle controls) to 20 % (rotenone group). Increase in the average time to initiate a step from 5 s to 11 s.	Fleming et al. 2004	Rats + rotenone 2.5 mg/kg for 21 days i.v. or s.c.
Loss of striatal DA fibers by 54 % Loss of DA neurons by 28.5 %	Spontaneous locomotor activity after 1 week 100 % (control) 55 % (rotenone)	Höglinger et al. 2003	Rats + rotenone (2.5 mg/kg/day for 28 days
Mouse models
Subacute model: Striatal DA dropped from 11 ng/mg (control) to 2.5 ng/mg (MPTP) after 3 days. 3H-DA striatal uptake reduced from 2.9 pmol/mg (control) to 1.3 pmol/mg after 3 days of MPTP. Total nigrostriatal TH cell count was not affected. Chronic model: Striatal DA content reduced from 13 ng/ml down to 0.5 ng/ml at 1 week after MPTP treatment. 3H-DA uptake in the striatum reduced from 3 pmol/mg to 1 pmol/mg 1 week after start of MPTP treatment. TH staining in the nigrostriatal system reduced by ca. 50 % 1 week after initiation of MPTP treatment.	Subacute model: Rotarod performance reduced from 1800 AUC (control) down to 1500 AUC (MPTP). Chronic model: Rotarod performance reduced from 1800 AUC (control) to 1250 AUC (1 week after initiation of MPTP treatment)	Petroske et al. 2001	Mouse + MPTP Subacute model: 25 mg/kg MPTP 1x days for 5 days Chronic model: MPTP (25 mg/kg + 250 mg/kg probenizid) in 3.5 day intervals for maximal 5 weeks
Reduction in TH staining intensity of at least 50 % required for detectable influence on motor performance. TH density in the nigrostriatal system correlated with the decline of rotarod performance (r2 = 0.87)	Rotarod performance reduced from 1250 AUC to 200 AUC Time on rod at a speed of 20 rpm: 125 s in controls, 25 s in MPTP animals	Rozas et al. 1998	Mouse + MPTP
Monkey models
Approx. 50 % loss of TH positive neurons in the SNpc. DA content in the caudate nucleu reduced to < 10 %; DA content of the putamen ca. 10 % compared with control	Mean duration in the bradykinesia test increased from 3 sec. (day 0) to 19 sec. at day 15	Bezard et al. 2001	Macaca + MPTP i.v. 0.2 mg/kg daily for 15 days
Human
18F-dopa influx rate constants (Ki) Midbrain: Control: 0.008 Early PD: 0.008 Adv. PD: 0.006 Right putamen: Control: 0.017 Early PD: 0.006 Adv. PD: 0.0036 Left putamen: Control: 0.017 Early PD: 0.0096 Adv. PD: 0.005	Early PD: UPDRS: 9 +/- 3 Adv. PD: UPDRS: 41+/- 15	Rakshi et al. 1999	Human PD patients
Putamen influx (Ki/min) detected by 18F-dopa control: 0.0123 asympt. PD: 0.0099 symptom. PD: 0.007	Symptom. PD patients: mean UPDRS: 15.1 +/- 7.5 Correlation between total UPDRS and putamen Ki: r = -0.41	Morrish et al. 1995	Human PD
Uptake of 18F-DTBZ (VMAT2 tracer) reduced by: 20-36 % (caudate) 45-80 % (putamen) 31 % (SN)	UPDRS total: 12.1 +/- 7.1 Hoehn and Yahr : 1.0 +/- 0.1	Lin et al. 2014	Human PD
Caudate nucleus Ki/min Control: 0.011 PD group 3: 0.0067 Putamen Ki/min Control: 0.011 PD group 3: 0.0043	UPDRS: 50 +/- 11.6 in PD group 3	Broussolle et al. 1999	Human PD
Reduction in 18F-CFT uptake in the posterior putamen (by 18 %); in the anterior putamen (by 28 %); in the caudate nucleus (by 51 %)	Correlation between total motor score of the UPDRS and 18F-CFT uptake: Posterior putamen: r = -0.62 Anterior putamen: r = -0.64 Caudate nucleus: r = -0.62	Rinne et al. 1999	Human PD
123I-CIT SPECT values in controls and PD cases with a Hoehn and Yahr rating of 2-2.5: Putamen (ipsilateral): Control: 6.13 PD: 1.84 Caudate (ipsilateral): Control: 6.93 PD: 3.66 Striatum (ipsilateral): Control: 6.28 PD: 2.33	Correlation coefficient between striatal 123I-CIT binding and: Str. (ipsilateral) and Bradykinesia: r = -0.61 Str. (ipsilateral) and Rigidity: r = -0.46 Str. (ipsilateral) and UPDRS: r = -0.79	Tissingh et al. 1998	Human PD
Binding ration striatum/cerebellum detected by 123I-CIT / SPECT Control: 8.71 +/- 1.54 PD: 4.49 +/- 1.86	Correlation between 123I-CIT binding to DAT and PD motor symptoms rated according to the Hoehn and Yahr scale: r = -0.75 Correlation according to the UPDRS: r = -0.49	Asenbaum et al. 1997	Human PD
Uptake of 123I-CIT in the putamen reduced to 54 %; uptake into the caudate nucleus reduced to 65 %	Correlation between CIT uptake in the putamen and Hoehn and Yahr stage: r = -0. 79	Rinne et al. 1995	Human PD
Decline in nigrostriatal DAT assed by 123I-CIT SPECT in PD patients	Correlation coefficients for 123I-CIT uptake in the striatum and: UPDRS: r =-0.54 Bradykinesia: r = -0.5 Rigidity: r = -0.27 Tremor: r = -0.3 Correlation coefficients for 123I-CIT uptake in the caudate and: UPDRS: r =-0.5 Bradykinesia: r = -0.43 Rigidity: r = -0.27 Tremor: r = -0.26 Correlation coefficients for 123I-CIT uptake in the putamen and: UPDRS: r =-0.57 Bradykinesia: r = -0.53 Rigidity: r = -0.29 Tremor: r = -0.37	Benamer et al. 2000	Human PD

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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

Parkinonian disorders are generally recognized as progressive age-related human neurodegenerative diseases more prevalent in males. However, the anatomy and function of the nigrostriatal pathway is conserved across mammalian species (Barron et al. 2010) and no sex and species restrictions were evidenciated using the chemical stressors rotenone and MPTP. It should be noted that animal behaviour models can only be considered as surrogates of human motor disorders as occuring in Parkinson's disease.