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See detailGenetic causes of Parkinson's disease: extending the pathway.
Riess, O.; Krüger, Rejko UL; Hochstrasser, H. et al

in Journal of neural transmission. Supplementum (2006), (70), 181-9

The functional characterization of identified disease genes in monogenic forms of Parkinson's disease (PD) allows first insights into molecular pathways leading to neurodegeneration and dysfunction of the ... [more ▼]

The functional characterization of identified disease genes in monogenic forms of Parkinson's disease (PD) allows first insights into molecular pathways leading to neurodegeneration and dysfunction of the nigrostriatal system. There is increasing evidence that disturbance of the ubiquitin proteasome pathway is one important feature of this process underscoring the relevance of protein misfolding and accumulation in the neurodegenerative process of PD. Other genes are involved in mitochondrial homeostasis and still others link newly identified signalling pathways to the established paradigm of oxidative stress in PD. Additional factors are posttranslational modifications of key proteins such as phosphorylation. Also, molecular data support the role of altered iron metabolism in PD. Here we describe known genes and novel genetic susceptibility factors and define their role in neurodegeneration. [less ▲]

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See detailScreening for mutations in synaptotagmin XI in Parkinson's disease.
Glass, A. S.; Huynh, D. P.; Franck, Th et al

in Journal of neural transmission. Supplementum (2004), (68), 21-8

Parkinson's disease (PD) is characterized by selective degeneration of neurons in the substantia nigra and subsequent dysfunction of dopaminergic neurotransmission. Genes identified in familial forms of ... [more ▼]

Parkinson's disease (PD) is characterized by selective degeneration of neurons in the substantia nigra and subsequent dysfunction of dopaminergic neurotransmission. Genes identified in familial forms of PD encode proteins that are linked to the ubiquitin-proteasome system indicating the pathogenic relevance of disturbed protein degradation in PD. Some of them, i.e. alpha-synuclein, parkin and synphilin-1, have been implicated in presynaptic neurotransmission based on their localization in synaptic vesicles. Synaptotagmin XI is linked to the pathogenesis of PD based on its identification as a substrate of the ubiquitin-E3-ligase parkin. Moreover synaptotagmin XI is involved in the maintainance of synaptic function and represents a component of Lewy bodies (LB) in brains of PD patients. Therefore, we performed a detailed mutation analysis of the synaptotagmin XI gene in a large sample of 393 familial and sporadic PD patients. We did not find any disease causing mutations arguing against a major role of mutations in the synaptotagmin XI gene in the pathogenesis of PD. [less ▲]

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See detailSelegiline as immunostimulant--a novel mechanism of action?
Muller, T.; Kuhn, W.; Krüger, Rejko UL et al

in Journal of neural transmission. Supplementum (1998), 52

In clinical studies the MAO-B inhibitor selegiline appears to slow the progression of neurological deficits in Parkinson's disease (PD) and the cognitive decline in Alzheimer's disease (AD). The ... [more ▼]

In clinical studies the MAO-B inhibitor selegiline appears to slow the progression of neurological deficits in Parkinson's disease (PD) and the cognitive decline in Alzheimer's disease (AD). The mechanisms of action remain unclear. Several lines of evidence indicate an immune-mediated pathophysiology of PD and AD. According to animal trials, selegiline increases the survival rate of immune suppressed mice. Stimulation of the immune response to bacterial or viral infection or in chronic inflammatory processes in managed by an increased synthesis of the cytokines interleukin-1 beta (IL-1 beta) and subsequent interleukin-6 (IL-6). Outcome of viral or bacterial infections in the brain highly correlates with levels of the cytotoxic cytokine tumor-necrosis-factor-alpha (TNF). The aim of our study was to characterize the influence of selegiline on the biosynthesis of IL-1 beta, IL-6 and TNF in human peripheral blood mononuclear cells (PBMC) from healthy blood donors. After isolation and washing PBMC were cultured without and with selegiline in three different concentrations (0.01 mumol/l, 0.001 mumol/l, 0.0001 mumol/l) in a humidified atmosphere (7% CO2). Then cultures were centrifuged and supernatants were collected for IL-1 beta, IL-6 and TNF ELISA-assays. Treatment of cultured PBMC with various concentrations induced an increased synthesis of IL-1 beta (ANOVA F = 9.703, p = 0.0007), IL-6 (ANOVA F = 20.648, p = 0.0001) and a reduced production of TNF (ANOVA F = 3.770, p = 0.040). These results indicate, that the influence of selegiline on the cytokine biosynthesis may also contribute to its putative neuroprotective properties. [less ▲]

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