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Degeneration of dopaminergic neurons of the nigrostriatal pathway leads to Parkinsonian motor deficits
Key Event Relationship Overview
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||TFHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
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 Supporting this KER
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
- 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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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