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Zebrafish have become an important model organism to study the genetic control of vertebrate nervous system development. Here, we present an overview on the formation of dopaminergic neuronal groups in zebrafish and compare the positions of DA neurons in fish and mammals using the neuromere model of the vertebrate brain. Based on mutant analysis, we evaluate the role of several signaling pathways in catecholaminergic neuron specification. We further discuss the prospect of identifying novel genes involved in dopaminergic development through forward genetics mutagenesis screens.

Striatal dopamine loss in Parkinson’s Disease (PD) sets into play a variety of compensatory responses to help counter dopamine depletion. Most of these changes involve surviving dopamine neurons, but there are also changes in striatal medium spiny neurons (MSNs), which are the major target of dopamine axons. Among these changes are decreases in MSN dendritic length and spine density, which may dampen excessive corticostriatal glutamatergic drive onto MSNs that occurs secondary to dopamine loss. An increasing knowledge of dendritic changes in PD suggests strategies for tracking progressive worsening of symptoms and is opening new ideas on novel therapeutic strategies for PD.

The discovery of the nigrostriatal DA system in the rat was made possible by the highly specific and sensitive histochemical fluorescence method of Falck and Hillarp in combinations with electrolytic lesions in the substantia nigra and removal of major parts of the neostriatum. Recent work on DA neuron evolution shows that in the Bottlenose Dolphin the normal DA cell groups of the substantia nigra are very cell sparse, while there is a substantial expansion of the A9 medial and A10 lateral subdivisions forming an impressive “ventral wing” in the posterior substantia nigra. The nigrostriatal DA pathway mainly operates via Volume Transmission. Thus, DA diffuses along concentration gradients in the ECF to reach target cells with high affinity DA receptors. A novel feature of the DA receptor subtypes is their physical interaction in the plasma membrane of striatal neurons forming receptor mosaics (RM) with the existence of two types of RM. The “functional decoding unit” for DA is not the single receptor, but rather the RM that may affect not only the integration of signals in the DA neurons but also their trophic conditions. In 1991 A2A receptor antagonists were indicated to represent novel antiparkinsonian drugs based on the existence of A2A/D2 receptor-receptor interactions and here P2X receptor antagonists are postulated to be neuroprotective drugs in treatment of Parkinson’s Disease.

In this paper we evaluate the hypothesis of a possible link between the degree of axonal collateralization of neurons located within the different components of basal ganglia and the vulnerability of these neurons to neurodegenerative or neurotoxic events. Our results stemmed from single-cell labeling experiments in rodents and primates, immunohistochemical study of the dopaminergic nigrostriatal pathway in parkinsonian monkeys, and immunocytological analysis of the human striatum in normal individuals and in patients with Huntington’s disease. Our results indicate that projection neurons within virtually all basal ganglia components are endowed with a widespread and highly collateralized axon that yields a fixed number of terminals. Such a high degree of axonal collateralization allows exquisitely precise interactions between the various basal ganglia nuclei. However, the maintenance of this unique morphological trait implies high-energy consumption and renders basal ganglia neurons highly vulnerable to neurodegenerative, metabolic or neurotoxic insults.

Parkinson’s disease (PD) is a multisystem disorder in which predisposed neuronal types in specific regions of the human peripheral, enteric, and central nervous systems become progressively involved. A staging procedure for the PD-related inclusion body pathology (i.e., Lewy neurites and Lewy bodies) in the brain proposes that the pathological process begins at two sites and progresses in a topographically predictable sequence in 6 stages. During stages 1–2, the inclusion body pathology remains confined to the medulla oblongata, pontine tegmentum, and anterior olfactory structures. In stages 3–4, the basal mid- and forebrain become the focus of the pathology and the illness reaches its symptomatic phase. In the final stages 5–6, the pathological process is seen in the association areas and primary fields of the neocortex. To date, we have staged a total of 301 autopsy cases, including 106 cases with incidental pathology and 176 clinically diagnosed PD cases. In addition, 163 age-matched controls were examined. 19 of the 301 cases with PD-related pathology displayed a pathological distribution pattern of Lewy neurites and Lewy bodies that diverged from the staging scheme described above. In these cases, olfactory structures and the amygdala were predominantly involved in the virtual absence of brain stem pathology. Most of the divergent cases (17/19) had advanced concomitant Alzheimer’s disease-related neurofibrillary changes (stages IV-VI).

Clinical Parkinson’s disease (PD) is a well-characterised syndrome that benefits significantly from dopamine replacement therapies. A staging procedure for sporadic PD pathology was developed by Braak et al. assuming that the abnormal deposition of α-synuclein indicates the intracellular process responsible for clinical PD. This paradigm has merit in corralling patients with similar cellular mechanisms together and determining the potential sequence of events that may herald the clinical syndrome. Progressive pathological stages were identified — 1) preclinical (stages 1–2), 2) early (stages 3–4, 35% with clinical PD) and 3) late (stages 5–6, 86% with clinical PD). However, preclinical versus early versus late-stage cases should on average be progressively older at the time of sampling, a feature not observed in the cohort analysed. In this cohort preclinical cases would have developed extremely late-onset PD compared with the other types of cases analysed. While the staging scheme is a valuable concept, further development is required.

The Ubiquitin Proteasome System is a multi-enzymatic pathway which degrades polyubiquinated soluble cytoplasmic proteins. This biochemical machinery is impaired both in sporadic and inherited forms of Parkinsonism. In the present paper we focus on the role of the pre-synaptic protein α-synuclein in altering the proteasom based on the results emerging from experimental models showing a mechanistic chain of events between altered α-synuclein, proteasome impairment and formation of neuronal inclusions and catecholamine cell death.

Protein aggregates such as Lewy bodies have done much for the scientists in the field of neurodegenerative diseases: They have highlighted the affected cell populations and they have trapped the mutant disease protein. Instead of a good reputation, however, protein aggregates have received incriminations, because they are consistently seen at the site of crime. Reviewing the arguments, crucial evidence has become known that (a) the specific neuronal pathology precedes the appearance of protein aggregates in mouse models of disease, (b) the neurodegenerative disease in patients occurs with comparable severity when visible protein aggregates remain absent, (c) the neurotoxicity in vitro is best reproduced by oligomers, not polymers of the mutant disease protein. Is it feasible that protein aggregates are inert byproducts of the disease protein malconformation, or that they even represent beneficial cellular efforts to sequestrate the soluble toxic disease protein, together with normal or aberrant interactor proteins? Whatever the answer will be, one positive role of protein aggregates seems clear: In contrast to earlier speculations that random cytoplasmic proteins are trapped within the aggregates, scientists now believe that the composition of the Lewy body reflects the network of interactions between crucial players in disease pathogenesis, such as the PARK1, PARK2 and PARK5 protein.

The massive, early and relatively circumscribed death of the dopaminergic neurons of the substantia nigra in Parkinson’s disease has not yet been adequately explained. The characteristic feature of this brain region is the presence of neuromelanin pigment within the vulnerable neurons. We suggest that neuromelanin in the Parkinson’s disease brain differs to that in the normal brain. The interaction of neuromelanin with iron has been shown to differ in the parkinsonian brain in a manner consistent with an increase in oxidative stress. Further, we suggest an interaction between the lipoprotein α-synuclein and lipidated neuromelanin contributes to the aggregation of this protein and cell death in Parkinson’s disease. The available data suggest that the melaninisation of the dopaminergic neurons of the substantia nigra is a critical factor to explain the vulnerability of this brain region to early and massive degeneration in Parkinson’s disease.

In Parkinson’s disease (PD), the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin (NM), is the characteristic pathological feature. The role of NM in the cell death of dopamine neurons has been considered either to be neurotoxic or neuroprotective, but the precise mechanism has never been elucidated. In human brain, NM is synthesized by polymerization of dopamine and relating quinones, to which bind heavy metals including iron. The effects of NM prepared from human brain were examined using human dopaminergic SH-SY5Y cells. It was found that NM inhibits 26S proteasome activity through generation of reactive oxygen and nitrogen species from mitochondria. The mitochondrial dysfunction was also induced by oxidative stress mediated by iron released from NM. NM accumulated in dopamine neurons in ageing may determine the selective vulnerability of dopamine neurons in PD.