Dopaminergic neuronal pathway

Nigrostriatal tract The major dopaminergic neuronal pathway linking midbrain and forebrain basal ganglia. 

The nigrostriatal tract is one of the four main dopaminergic pathways in the central nervous system. About 75% of the dopamine in the brain occurs in the nigrostriatal pathway with its cell bodies in the substantia nigra, whose axons project in the corpus striatum. Degeneration of the dopaminergic neurons in the nigrostriatal system results in Parkinsons disease. 

Unlike many chemicals in the brain, neurotransmitters are not homogeneously distributed, but concentrated in certain regions. For example, almost two-thirds of the dopamine in the brain is found in the bilateral nigrostriatal (mesostriatal) tract (pathway), where the neuronal cell bodies are located in the substantia nigra and the axons terminate in the corpus striatum. When over 85% of these dopaminergic neurons are lost, the characteristic motor dysfunction of Parkinson s disease is seen. 

Drugs stimulate receptors on the cell bodies of dopaminergic neurons causing dopamine release and stimulating postsynaptic dopamine receptors in the nucleus accumbens, supposedly resulting in the perception of pleasure [1]. Other hypotheses suggest that these mesolimbic dopaminergic pathways are necessary for the... 

Figure 14.19 Simplified schematic overview of the directed differentiation of human embryonic stem cells to form differentiated dopamine like neurons. The full pathway details are available in Yan, Y., Yang, D., Zarnowska, E.D., Du, Z., Werbel, B., Valliere, C., etai 2005. Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 23, 781-790. FGF fibroblast growth factor SHH sonic hedgehog (a regulatory protein)...

Figure 2. Model-2. Parkin is linked to sporadic PD as well as AR-JP. a-Syn, a-synuclein. For details including environmental stress, neurotoxin, ROS, qualitycontrolling E3, UCH-Ll, CHIP, UPR, CDCrel-1, initiation , and promotion , see text. In this model, impairment of protein degradation pathway downstream of ubiquitination results in accumulation of ubiquitinated protein(s) and non-ubiquitinated protein(s), i.e., aggregate formation (LB). At present, it is unknown whether parkin is involved in LB formation or LB causes dopaminergic neuron death, however it is currently clear that LB formation is not directly linked to neuronal death and pathogenesis of PD as shown by a dotted line (see text). Note that AR-JP can also be explained by model-2, if parkin operates as a qualitycontrolling E3.

In this review, we proposed two models in AR-JP model-1 for the function of parkin whose dysfunction causes AR-JP (Fig. 1) and modeI-2, which hypothesizes that AR-JP is an alternative form of sporadic PD (Fig. 2). In model-1, we predict that parkin target X is a factor whose accumulation can activate the death-signalling pathway, which is only present in dopaminergic neurons, as a sequence to reduced E3-function of parkin. In contrast, in model-2, we predict that parkin is a member of the quality-controlling E3 family and is involved in the LB formation. At present, we do not know which model is correct, but we favor the latter scenario shown in model-2, because the presence of SN-specific substrate X seems unlikely and it is plausible that parkin is present in LB. However, to date many neuropathologists follow the former model-1 and believe that AR-JP differs from sporadic PD based on pathological evidence, i.e., LB must be detected at postmortem examination in the surviving neurons of PD. 

The mechanism of the neurological symptoms in Parkinson s disease was discovered from the ability of reserpine to cause akinesia in humans by the depletion of central catecholamine stores. The dopamine levels in patients who died from parkinsonism were found to be extremely low because of deterioration of the dopaminergic neuronal cell bodies and the pathways connecting the substantia nigra with the corpus striatum. 

Cells damaged by disease, e.g., dopaminergic neurons in Parkinson disease, may die by apoptosis.147a b A second form of self-destruction occurs when an axon is cut.147b Failure of the elaborate network of mechanism for repair of DNA and maintenance of the genome normally leads to apoptosis. In cancer essential steps in the apoptosis pathway are often inactivated.147c... 

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