This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 910


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
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 High 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

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 Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
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 mechanistic understanding of striatal DA and its regulatory role in the extrapyramidal motor control system is well established (Alexander et al. 1986; Penney et al. 1986; Albin et al. 1989; DeLong et al. 1990; Obeso et al. 2008; Blandini et al. 2000). The selective degeneration of DA neurons in the SNpc (and the subsequent decline in striatal DA levels) have been known to be linked to PD symptoms for more than 50 years (Ehringer et al. 1960). The reduction of DA in the striatum is characteristic for all etiologies of PD (idiopathic, familial, chronic manganese exposure) and related parkinsonian disorders (Bernheimer et al. 1973), and it is not observed in other neurodegenerative diseases, such as Alzheimer’s or Huntington’s Diseases (Reynolds et al. 1986). In more progressive stages of PD, not only a loss of DA neuronal terminals in the striatum, but also a degeneration of the entire DA neuron cell bodies in the substantia nigra pars compacta (SNpc) was detected (Leenders et al. 1986; Bernheimer et al. 1973). The different forms of PD exhibit variations in the degradation pattern of the SNpc DA neurons. In idiopathic PD, for example, the putamen is more severely affected than the caudate nucleus (Moratalla et al. 1992; Snow et al. 2000). All different PD forms however are characterized by the loss in striatal DA that is paralleled by impaired motor output (Bernheimer et al. 1973). Characteristic clinical symptoms of motor deficit (bradykinesia, tremor, or rigidity) of PD are observed when more than 80 % of striatal DA is depleted (Koller et al. 1992). These findings on the correlation of a decline in striatal DA levels as a consequence of SNpc DA neuronal degeneration with the onset of clinical PD symptoms in man provide the rationale for the current standard therapies that aim to supplement striatal DA, either by the application of L-DOPA, or by a pharmacological inhibition of the endogenous DA degradation-enzyme monoaminde oxidase B (MAO-B). These treatments result in an elevation of striatal DA that is correlated with an improvement of motor performance (Calne et al 1970). The success of these therapies in man as well as in experimental animal models clearly confirms the causal role of dopamine depletion for PD motor symptoms.

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
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

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.


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

Aizman O, Brismar H, Uhlén P, Zettergren E, Levey AI, Forssberg H, Greengard P, Aperia A (2000) Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons. Nat Neurosci. 3(3):226-30.

Alam M, Schmidt WJ (2002) Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res. 136(1):317-24.

Alam M, Schmidt WJ (2004) L-DOPA reverses the hypokinetic behaviour and rigidity in rotenone-treated rats. Behav Brain Res. 153(2):439-46. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci. 12(10):366-75.

Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 9:357-81.

Asenbaum S, Brücke T, Pirker W, Podreka I, Angelberger P, Wenger S, Wöber C, Müller C, Deecke L (1997) Imaging of dopamine transporters with iodine-123-beta-CIT and SPECT in Parkinson's disease. J Nucl Med. 38(1):1-6.

Aziz TZ, Peggs D, Sambrook MA, Crossman AR (1991) Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord. 6(4):288-92.

Baik JH, Picetti R, Saiardi A, Thiriet G, Dierich A, Depaulis A, Le Meur M, Borrelli E (1995) Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature. 377(6548):424-8.

Benamer HT, Patterson J, Wyper DJ, Hadley DM, Macphee GJ, Grosset DG (2000) Correlation of Parkinson's disease severity and duration with 123I-FP-CIT SPECT striatal uptake. Mov Disord. 15(4):692-8.

Bergman H, Wichmann T, DeLong MR (1990) Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 249(4975):1436-8.

Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci. 20(4):415-55.

Bezard E, Dovero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, Crossman AR, Bioulac B, Brotchie JM, Gross CE (2001) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease. J Neurosci. 21(17):6853-61.

Blandini F, Nappi G, Tassorelli C, Martignoni E (2000) Functional changes of the basal ganglia circuitry in Parkinson's disease. Prog Neurobiol. 62(1):63-88.

Blesa J, Pifl C, Sánchez-González MA, Juri C, García-Cabezas MA, Adánez R, Iglesias E, Collantes M, Peñuelas I, Sánchez-Hernández JJ, Rodríguez-Oroz MC, Avendaño C, Hornykiewicz O, Cavada C, Obeso JA (2012) The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: a PET, histological and biochemical study. Neurobiol Dis. 48(1):79-91.

Boraud T, Bezard E, Guehl D, Bioulac B, Gross C (1998) Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey. Brain Res. 787(1):157-60.

Bové J, Perier C (2012) Neurotoxin-based models of Parkinson's disease. Neuroscience. 211:51-76.

Broussolle E, Dentresangle C, Landais P, Garcia-Larrea L, Pollak P, Croisile B, Hibert O, Bonnefoi F, Galy G, Froment JC, Comar D (1999) The relation of putamen and caudate nucleus 18F-Dopa uptake to motor and cognitive performances in Parkinson's disease. J Neurol Sci. 166(2):141-51.

Calne DB, Sandler M (1970) L-Dopa and Parkinsonism. Nature. 226(5240):21-4.

Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT (2009) A highly reproducible rotenone model of Parkinson's disease. Neurobiol Dis. 34(2):279-90.

Ceballos-Baumann AO, Obeso JA, Vitek JL, Delong MR, Bakay R, Linazasoro G, Brooks DJ (1994) Restoration of thalamocortical activity after posteroventral pallidotomy in Parkinson's disease. Lancet. 344(8925):814.

DeLong MR (1990) Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 13(7):281-5.

Earle KM (1968) Studies on Parkinson's disease including x-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol. 27(1):1-14.

Ehringer H, Hornykiewicz O (1960) Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Klin Wochenschr. 38:1236-9.

Filion M, Tremblay L (1991) Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res. 547(1):142-51.

Fleming SM, Zhu C, Fernagut PO, Mehta A, DiCarlo CD, Seaman RL, Chesselet MF (2004) Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone. Exp Neurol. 187(2):418-29.

Gilmour TP, Lieu CA, Nolt MJ, Piallat B, Deogaonkar M, Subramanian T (2011) The effects of chronic levodopa treatments on the neuronal firing properties of the subthalamic nucleus and substantia nigra reticulata in hemiparkinsonian rhesus monkeys. Exp Neurol. 228(1):53-8.

Heimer G, Bar-Gad I, Goldberg JA, Bergman H (2002) Dopamine replacement therapy reverses abnormal synchronization of pallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of parkinsonism. J Neurosci. 2002 Sep 15;22(18):7850-5.

Höglinger GU, Féger J, Prigent A, Michel PP, Parain K, Champy P, Ruberg M, Oertel WH, Hirsch EC (2003) Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. J Neurochem. 84(3):491-502.

Hutchinson WD, Levy R, Dostrovsky JO, Lozano AM, Lang AE (1997) Effects of apomorphine on globus pallidus neurons in parkinsonian patients. Ann Neurol. 42(5):767-75.

Koller WC (1992) When does Parkinson's disease begin? Neurology. 42(4 Suppl 4):27-31

Kordower JH, Freeman TB, Chen EY, Mufson EJ, Sanberg PR, Hauser RA, Snow B, Olanow CW (1998) Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease. Mov Disord. 13(3):383-93.

Kordower JH, Freeman TB, Snow BJ, Vingerhoets FJ, Mufson EJ, Sanberg PR, Hauser RA, Smith DA, Nauert GM, Perl DP (1995) Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N Engl J Med. 332(17):1118-24.

Leenders KL, Palmer AJ, Quinn N, Clark JC, Firnau G, Garnett ES, Nahmias C, Jones T, Marsden CD (1986) Brain dopamine metabolism in patients with Parkinson's disease measured with positron emission tomography. J Neurol Neurosurg Psychiatry. 49(8):853-60.

Levy R, Dostrovsky JO, Lang AE, Sime E, Hutchison WD, Lozano AM (2001) Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease. J Neurophysiol. 86(1):249-60.

Limousin P, Brown RG, Jahanshahi M, Asselman P, Quinn NP, Thomas D, Obeso JA, Rothwell JC (1999) The effects of posteroventral pallidotomy on the preparation and execution of voluntary hand and arm movements in Parkinson's disease. Brain. 122 ( Pt 2):315-27.

Lin SC, Lin KJ, Hsiao IT, Hsieh CJ, Lin WY, Lu CS, Wey SP, Yen TC, Kung MP, Weng YH (2014) In vivo detection of monoaminergic degeneration in early Parkinson disease by (18)F-9-fluoropropyl-(+)-dihydrotetrabenzazine PET. J Nucl Med. 55(1):73-9.

Lloyd KG, Davidson L, Hornykiewicz O (1975) The neurochemistry of Parkinson's disease: effect of L-dopa therapy. J Pharmacol Exp Ther. 195(3):453-64.

Luthman J, Fredriksson A, Sundström E, Jonsson G, Archer T (1989) Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behav Brain Res. 33(3):267-77.

Mitchell IJ, Clarke CE, Boyce S, Robertson RG, Peggs D, Sambrook MA, Crossman AR (1989) Neural mechanisms underlying parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience. 32(1):213-26.

Moratalla R, Quinn B, DeLanney LE, Irwin I, Langston JW, Graybiel AM (1992) Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A. 89(9):3859-63

Morrish PK, Sawle GV, Brooks DJ (1995) Clinical and [18F] dopa PET findings in early Parkinson's disease. J Neurol Neurosurg Psychiatry. 59(6):597-600.

Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, Blesa FJ, Guridi J, Marin C, Rodriguez M (2008) Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease. Mov Disord. Suppl 3:S548-59.

Obeso JA, Rodríguez-Oroz MC, Rodríguez M, Lanciego JL, Artieda J, Gonzalo N, Olanow CW (2000) Pathophysiology of the basal ganglia in Parkinson's disease. Trends Neurosci. 23(10 Suppl):S8-19.

Papa SM, Desimone R, Fiorani M, Oldfield EH. (1999) Internal globus pallidus discharge is nearly suppressed during levodopa-induced dyskinesias. Ann Neurol. 46(5):732-8.

Penney JB Jr, Young AB (1986) Striatal inhomogeneities and basal ganglia function. Mov Disord. 1(1):3-15.

Perese DA, Ulman J, Viola J, Ewing SE, Bankiewicz KS (1989) A 6-hydroxydopamine-induced selective parkinsonian rat model. Brain Res. 494(2):285-93.

Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS (2001) Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience. 106(3):589-601.

Pirker W (2003) Correlation of dopamine transporter imaging with parkinsonian motor handicap: how close is it? Mov Disord. 18 Suppl 7:S43-51.

Przedborski S, Levivier M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, Togasaki DM (1995) Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience. 67(3):631-47.

Rakshi JS, Uema T, Ito K, Bailey DL, Morrish PK, Ashburner J, Dagher A, Jenkins IH, Friston KJ, Brooks DJ (1999) Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease A 3D [(18)F]dopa-PET study. Brain. 122 ( Pt 9):1637-50.

Reynolds GP, Garrett NJ (1986) Striatal dopamine and homovanillic acid in Huntington's disease. J Neural Transm. 65(2):151-5.

Rinne JO, Kuikka JT, Bergström KA, Rinne UK (1995) Striatal dopamine transporter in different disability stages of Parkinson's disease studied with [(123)I]beta-CIT SPECT. Parkinsonism Relat Disord. 1(1):47-51.

Rinne JO, Ruottinen H, Bergman J, Haaparanta M, Sonninen P, Solin O (1999) Usefulness of a dopamine transporter PET ligand [(18)F]beta-CFT in assessing disability in Parkinson's disease. J Neurol Neurosurg Psychiatry. 67(6):737-41.

Rozas G, López-Martín E, Guerra MJ, Labandeira-García JL (1998) The overall rod performance test in the MPTP-treated-mouse model of Parkinsonism. J Neurosci Methods. 83(2):165-75.

Snow BJ, Vingerhoets FJ, Langston JW, Tetrud JW, Sossi V, Calne DB (2000) Pattern of dopaminergic loss in the striatum of humans with MPTP induced parkinsonism. J Neurol Neurosurg Psychiatry. 68(3):313-6.

Tissingh G, Bergmans P, Booij J, Winogrodzka A, van Royen EA, Stoof JC, Wolters EC (1998) Drug-naive patients with Parkinson's disease in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [123I]beta-CIT SPECT. J Neurol. 245(1):14-20.

Tolwani RJ, Jakowec MW, Petzinger GM, Green S, Waggie K (1999) Experimental models of Parkinson's disease: insights from many models. Lab Anim Sci. 49(4):363-71.

Varastet M, Riche D, Maziere M, Hantraye P (1994) Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in Parkinson's disease. Neuroscience. 63(1):47-56.

Widner H, Tetrud J, Rehncrona S, Snow B, Brundin P, Gustavii B, Björklund A, Lindvall O, Langston JW. (1992) Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med. 327(22):1556-63.