Journal of Neural Transmission-supplement最新文献

In order to reach a deeper insight into the mechanism of diethyldithiocarbamate (DDC)-induced enhancement of MPTP toxicity in mice, we showed that CYP450 (2E1) inhibitors, such as diallyl sulfide (DAS) or phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration in C57/bl mice. Furthermore we showed that CYP 2E1 is present in the brain and in the basal ganglia of mice (Vaglini et al., 2004). However, because DAS and PIC are not selective CYP 2E1 inhibitors and in order to provide direct evidence for CYP 2E1 involvement in the enhancement of MPTP toxicity, CYP 2E1 knockout mice (GONZ) and wild type animals (SVI) of the same genetic background were treated with MPTP or the combined DDC + MPTP treatment. In CYP 2E1 knockout mice, DDC pretreatment completely fails to enhance MPTP toxicity, although enhancement of MPTP toxicity was regularly present in the SVI control animals. The immunohistochemical study confirms our results and suggests that CYP 2E1 may have a detoxifying role.

Five men with advanced idiopathic Parkinson's disease (PD) were examined to assess the effect of low dose methylphenidate (MPD) on gait. The patients were tested during "off" state before and two hours after the intake of 10 mg MPD while walking an "8 trajectory". The total walking time, total freezing time, number of freezing episodes and the non-freezing walking time were assessed. The obtained data were compared by the Wilcoxon Signed Rank test with a type I error rate of 0.05. The results showed a statistically significant improvement in all gait parameters after MPD intake. Moreover, a good correlation in the grade of improvement for each individual gait characteristic was found. The study demonstrates that low dose of MPD may improve gait, and especially freezing, in patients with severe PD, without the need for exogenous L-dopa. The mechanism of MPD action in patients with advanced PD is further discussed.

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.

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 common neurodegenerative disorder that is characterized by the progressive loss of dopamine (DA) neurons. Accompanying the loss the of DA neurons is the accumulation of Lewy bodies and neurites, intracytoplasmic proteinaceous inclusions that contain alpha-synuclein, synphilin-1, components of the ubiquitin proteasomal pathway and parkin. Recent advances indicate that PD is due in some individuals to genetic mutations in alpha-synuclein, DJ-1, PINK-1, LRRK2, and parkin. Understanding the molecular mechanisms by which mutations in familial-linked genes cause PD holds great promise for unraveling the mechanisms by which DA neurons degenerate in PD. Parkin is E3-ubiquitin-protein ligase that ubiquitinates itself and promotes its own degradation. Familial associated mutations of parkin have impaired ubiquitin ligase function suggesting that this may be the cause of familial autosomal recessive PD. Parkin might be required for formation of Lewy bodies as Lewy bodies are absent in patients with parkin mutations. Parkin interacts with and ubiquitinates the alpha-synuclein interacting protein, synphilin-1. Formation of Lewy-body-like ubiquitin-positive cytosolic inclusions occurs upon coexpression of alpha-synuclein, synphilin-1 and parkin. Nitric oxide inhibits Parkin's E-3 ligase activity and its protective function by nitric oxide through S-nitrosylation both in vitro and in vivo. Nitrosative and oxidative stress link parkin function with the more common sporadic form of Parkinson's disease and the related alpha-synucleinopathy, DLBD. Development of new therapies for PD and other disorders associated with nitrosative and oxidative stress may follow the elucidation of the pathways by which NO S-nitrosylates and inhibits parkin. Moreover, parkin and alpha-synuclein are linked in common pathogenic mechanism through their interaction with synphilin-1 and parkin may be important for the formation of Lewy bodies.

Objectives: To elucidate the role of alpha-synuclein in the pathogenesis of Parkinson's disease (PD), both human alpha-synuclein transgenic mice and targeted overexpression of human alpha-synuclein in rat substantia nigra (SN) by viral vector-based methods have been studied, however little is known about the pathogenetic changes of dopaminergic neuron loss. Therefore, it is necessary to address whether the pathogenetic changes in the brains of patients with PD are recapitulated in these models.

Methods and results: We used the recombinant adeno-associated viral (rAAV) vector system for human alpha-synuclein gene transfer to rat SN and observed approximately 50% loss of dopaminergic neurons in SN at 13 weeks after infection. In the slower progression of neurodegeneration, we identified several important features in common with the pathogenesis of PD, such as phosphorylation of alpha-synuclein at Ser129 and activation of caspase-9. Both findings were also evident in cortical tissues overexpressing alpha-synuclein via rAAV.

Conclusions: Our results indicate that overexpression of alpha-synuclein via rAAV apparently recapitulates several important features of brains with PD and dementia with Lewy bodies (DLB), and thus alpha-synucleinopathy described here is likely to be an ideal model for the study of the pathogenesis of PD and DLB. This model is also useful for the gene therapy research.

Glial cell line-derived neurotrophic factor (GDNF) has been implicated in the protection of dopamine (DA) neurons from oxidative stress in animal models of Parkinson's disease (PD). We have now shown that GDNF can also protect against the effects of 6-hydroxydopamine (6-OHDA) in a dopaminergic cell line and in cultures of primary DA neurons prepared from rat substantia nigra (SN). This appears to involve a rapid and transient increase in the phosphorylation of several isoforms of extracellular signal-regulated kinase (ERK). Our evidence indicates that ERK activation also can be modulated by reactive oxygen species (ROS), including those generated by endogenous DA. Identification of the ways by which these pathways can be triggered should provide insights into the pathophysiology of PD, and may offer useful avenues for retarding the progression of the disorder.

Primary torsion dystonia (PTD) has a broad clinical spectrum, with earlier onset of symptoms associated with more generalized muscle involvement. The causes for most dystonia are unknown although several monogenic subtypes have been identified. One important genetic cause of PTD is DYT1; a three base pair deletion in this gene is a major cause for early-onset dystonia. Its identification has allowed the development of cellular and animal models; it has also permitted studies that identify both "manifesting" and "non-manifesting" DYT1 mutation carriers. These studies have expanded our understanding of clinical expression to include psychiatric symptoms and also have enabled imaging studies of endophenotypes. These advances provide a widened platform for future research.

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 alpha-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.