References of "Krüger, Rejko 50002143"
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See detailInvolvement of alpha-synuclein in Parkinson's disease and other neurodegenerative disorders.
Krüger, Rejko UL; Muller, T.; Riess, O.

in Journal of neural transmission (Vienna, Austria : 1996) (2000), 107(1), 31-40

A major step in the elucidation of the pathogenesis of neurodegenerative disorders was the identification of a mutation in the alpha-synuclein gene in autosomal dominant Parkinson's disease (PD). Alpha ... [more ▼]

A major step in the elucidation of the pathogenesis of neurodegenerative disorders was the identification of a mutation in the alpha-synuclein gene in autosomal dominant Parkinson's disease (PD). Alpha-synuclein is the main component of Lewy bodies (LB), the neuropathological hallmark of PD. Moreover, a fragment of alpha-synuclein (NAC) is the second major component of amyloid plaques in Alzheimer's disease (AD). Recent studies of other neurodegenerative disorders such as dementia with LB (DLB), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) also revealed intracellular accumulations of alpha-synuclein in affected brain regions. This may indicate that these disorders partially share common pathogenic mechanisms. Recent data provide first insights into the physiological function of alpha-synuclein and support the concept of an essential role of alpha-synuclein in neurodegeneration. Increasing knowledge on the pathogenic molecular mechanisms of neurodegeneration and of the pathophysiological function of alpha-synuclein in particular may influence future development of therapeutic strategies in neurodegenerative disorders. [less ▲]

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See detailPCR/SSCP detects reliably and efficiently DNA sequence variations in large scale screening projects.
Miterski, B.; Krüger, Rejko UL; Wintermeyer, P. et al

in Combinatorial chemistry & high throughput screening (2000), 3(3), 211-8

A simple and fast method with high reliability is necessary for the identification of mutations, polymorphisms and sequence variants (MPSV) within many genes and many samples, e.g. for clarifying the ... [more ▼]

A simple and fast method with high reliability is necessary for the identification of mutations, polymorphisms and sequence variants (MPSV) within many genes and many samples, e.g. for clarifying the genetic background of individuals with multifactorial diseases. Here we review our experience with the polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP) analysis to identify MPSV in a number of genes thought to be involved in the pathogenesis of multifactorial neurological disorders, including autoimmune diseases like multiple sclerosis (MS) and neurodegenerative disorders like Parkinson s disease (PD). The method is based on the property of the DNA that the electrophoretic mobility of single stranded nucleic acids depends not only on their size but also on their sequence. The target sequences were amplified, digested into fragments ranging from 50-240 base pairs (bp), heat-denatured and analysed on native polyacrylamide (PAA) gels of different composition. The analysis of a great number of different PCR products demonstrates that the detection rate of MPSV depends on the fragment lengths, the temperature during electrophoresis and the composition of the gel. In general, the detection of MPSV is neither influenced by their location within the DNA fragment nor by the type of substitution, i.e., transitions or transversions. The standard PCR/SSCP system described here provides high reliability and detection rates. It allows the efficient analysis of a large number of DNA samples and many different genes. [less ▲]

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See detailExtrapyramidal motor signs in degenerative ataxias.
Schols, L.; Peters, S.; Szymanski, S. et al

in Archives of neurology (2000), 57(10), 1495-500

BACKGROUND: Extrapyramidal motor signs (EPS) are well-known symptoms of degenerative ataxia. However, little is known about frequency and appearance of EPS in subtypes of ataxia. METHODS: We characterized ... [more ▼]

BACKGROUND: Extrapyramidal motor signs (EPS) are well-known symptoms of degenerative ataxia. However, little is known about frequency and appearance of EPS in subtypes of ataxia. METHODS: We characterized 311 patients with ataxia clinically and genetically. Course of the disease and EPS were investigated according to a standardized protocol. Diagnostic and prognostic impact of EPS in subtypes of ataxia was analyzed by Kaplan-Meier plots. RESULTS: Extrapyramidal motor signs occurred in all forms of ataxia, but frequency and type of EPS varied between genetically and clinically defined subtypes. Postural tremor in hereditary ataxias was typical for spinocerebellar ataxia type 2 (SCA2). Dystonia was generally rare in ataxias, but, if present, suggested SCA3. We observed a parkinsonian variant of SCA3 in which parkinsonism was present in the beginning of the disease and responded well to levodopa therapy, leading to diagnostic confusion. Parkinsonism in SCA3 was independent of CAG repeat length but ran in families, suggesting modifying genes. In idiopathic sporadic cerebellar ataxia (ISCA), EPS are more frequent in late-onset than in early-onset forms. In 50% of ISCA patients with parkinsonism, the diagnosis of multiple system atrophy remained questionable because of normal autonomic function. CONCLUSIONS: Extrapyramidal motor signs can help to predict the genetic subtype of ataxia. Extrapyramidal motor signs were more frequent in genetic subtypes in which basal ganglia affection has been demonstrated by postmortem studies. However, no type of EPS was specific for an underlying mutation. In ISCA, EPS are an adverse prognostic factor. Parkinsonism is especially associated with a more rapid course of the disease. Arch Neurol. 2000;57:1495-1500 [less ▲]

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See detailGenetic analysis of immunomodulating factors in sporadic Parkinson's disease.
Krüger, Rejko UL; Hardt, C.; Tschentscher, F. et al

in Journal of neural transmission (Vienna, Austria : 1996) (2000), 107(5), 553-62

Immunomodulating factors have been shown to play a role in the pathogenesis of Parkinson's disease (PD) by biochemical methods. In order to investigate functionally important genes of the tumor necrosis ... [more ▼]

Immunomodulating factors have been shown to play a role in the pathogenesis of Parkinson's disease (PD) by biochemical methods. In order to investigate functionally important genes of the tumor necrosis factor alpha (TNFalpha) pathway we studied the frequency of DNA polymorphisms in the interleukin 6 (IL6), the TNFalpha, and the TNFalpha receptor 1 (TNFR1) genes in 264 sporadic German PD patients and in 183 age and sex matched German healthy controls. Analyzing the TNFalpha-308 polymorphism we found heterozygous individuals carrying alleles 1 and 2 more frequently in patients with a relative risk of 1.56 (p = 0.046, p(c) = 0.13, chi2 = 3.98). In contrast, the frequency of the B/2 haplotype described by the TNFR1-609 and TNFRI+36 polymorphisms was significantly decreased in our PD patients group (p = 0.0097, p(c) = 0.048, chi2 = 6.69) with a relative risk reduced to 0.52. Our results suggest an involvement of immunomodulating factors in the pathogenesis of sporadic PD as revealed by a molecular genetic approach. [less ▲]

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See detailGenetic analysis of the alpha2-macroglobulin gene in early- and late-onset Parkinson's disease.
Krüger, Rejko UL; Menezes-Saecker, A. M.; Schols, L. et al

in Neuroreport (2000), 11(11), 2439-42

Recent association studies investigating polymorphisms in the alpha2-macroglobulin (A2M) gene provided evidence for an involvement of this protease inhibitor in the pathogenesis of Alzheimer's disease (AD ... [more ▼]

Recent association studies investigating polymorphisms in the alpha2-macroglobulin (A2M) gene provided evidence for an involvement of this protease inhibitor in the pathogenesis of Alzheimer's disease (AD). The partially overlapping pathology between AD and Parkinson's disease (PD) led us to investigate the role of A2M in PD. We performed association studies in a large sample of 328 German PD patients and 322 closely matched healthy controls. Analyzing the Val1000Ile polymorphism and a pentanucleotide deletion in the 5' splice site of exon 18 of the A2M gene we found an excess of homozygosity for the A2M deletion in early-onset PD (EOPD) patients (age at onset < 50 years) compared to late-onset PD (LOPD) patients (age at onset > 50 years; p = 0.008, p(p)c = 0.064, chi2 = 7.017). Therefore our data might indicate an age at onset modulating effect of the homozygous A2M deletion in PD. [less ▲]

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See detailAnalysis of the parkin deletion in sporadic and familial Parkinson's disease. Short communication.
Krüger, Rejko UL; Vieira-Sacker, A. M.; Kuhn, W. et al

in Journal of neural transmission (Vienna, Austria : 1996) (1999), 106(2), 159-63

Recently a mutation in the parking gene has been identified as the cause for an autosomal-recessively inherited form of early onset Parkinson's disease (EOPD). The disease causing minimal deletion has ... [more ▼]

Recently a mutation in the parking gene has been identified as the cause for an autosomal-recessively inherited form of early onset Parkinson's disease (EOPD). The disease causing minimal deletion has been defined as a homozygous exon 4 loss in the parkin gene among Japanese patients. We investigated 140 sporadic and familial EOPD patients of German ancestry for the exon 4 deletion in the parkin gene. None of our patients exhibited a homozygous deletion of exon 4, suggesting a minor role of this mutation for EOPD in Caucasians. Nevertheless a detailed mutation analysis is warranted to explore the overall significance of mutations in the parkin gene in EOPD. [less ▲]

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See detailThe alpha1-antichymotrypsin A-allele in German Parkinson disease patients.
Grasbon-Frodl, E. M.; Egensperger, R.; Kosel, S. et al

in Journal of neural transmission (Vienna, Austria : 1996) (1999), 106(7-8), 729-36

An increased frequency of the A-allele of the alpha-antichymotrypsin (ACT) gene has been recently described in Japanese patients suffering from Parkinson disease (PD). In the present study, we have ... [more ▼]

An increased frequency of the A-allele of the alpha-antichymotrypsin (ACT) gene has been recently described in Japanese patients suffering from Parkinson disease (PD). In the present study, we have analyzed 62 German PD patients with regard to their ACT and APOE genotypes and compared them to 53 controls without clinical or pathological evidence of neurodegenerative disease. The A-allele frequency was 47% in PD patients compared to 54% in control cases excluding ACT as a major susceptibility factor for PD in the Caucasian population. Yet, ACT-A allele frequencies were significantly different (p < 0.001) between Japanese and German controls. Therefore, although our data do not suggest that the alpha1-ACT polymorphism is a significant risk factor for the development of PD, a consideration of differences in genetic background seems warranted when evaluating susceptibility factors for neurodegenerative disease. [less ▲]

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See detailIncreased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein/apolipoprotein E genotype.
Krüger, Rejko UL; Vieira-Saecker, A. M.; Kuhn, W. et al

in Annals of neurology (1999), 45(5), 611-7

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is ... [more ▼]

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, alpha-synuclein (alpha-SYN) has been identified as the main component of Lewy bodies in sporadic PD, suggesting involvement in neurodegeneration via protein accumulation. The partially overlapping pathology of PD and Alzheimer's disease, as well as striking structural similarities of alpha-SYN and apolipoprotein E, which is a major risk factor for late-onset Alzheimer's disease, prompted us to investigate the influence of different alpha-SYN and apolipoprotein E alleles for developing sporadic PD. We performed association studies in 193 German PD patients and 200 healthy control subjects matched for age, sex, and origin. A polymorphism in the promoter region of the alpha-SYN gene (NACP-Rep1) as well as of the closely linked DNA markers D4S1647 and D4S1628 revealed significant differences in the allelic distributions between PD patients and the control group. Furthermore, the Apo epsilon4 allele but not the Th1/E47 promoter polymorphism of the apolipoprotein E gene was significantly more frequent among early-onset PD patients (age at onset, <50 years) than in late-onset PD. Regarding the combination of the Apo epsilon4 allele and allele 1 of the alpha-SYN promoter polymorphism, a highly significant difference between the group of PD patients and control individuals has been found, suggesting interactions or combined actions of these proteins in the pathogenesis of sporadic PD. PD patients harboring this genotype have a 12.8-fold increased relative risk for developing PD during their lives. [less ▲]

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See detailGenetic dissection of familial Parkinson's disease.
Riess, O.; Jakes, R.; Krüger, Rejko UL

in Molecular medicine today (1998), 4(10), 438-44

In the past few years, the genetic contribution to Parkinson's disease (PD) has gained major attention and has resulted in the identification of the first mutant gene, called alpha-synuclein, involved in ... [more ▼]

In the past few years, the genetic contribution to Parkinson's disease (PD) has gained major attention and has resulted in the identification of the first mutant gene, called alpha-synuclein, involved in the pathogenesis of autosomal-dominant PD. alpha-Synuclein is a major component of Lewy bodies, which are a neuropathological feature of PD. Furthermore, deletions in the parkin gene have been identified as the primary cause in rare forms of autosomal-recessive juvenile PD. The elucidation of polygenic changes in the dopamine pathway, mitochondrial dysfunction, and metabolism of xenobiotics is now technically possible by means of association and genotype studies. The increasing knowledge of the pathogenesis of PD at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression. [less ▲]

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See detailSpinocerebellar ataxia type 6: genotype and phenotype in German kindreds.
Schols, L.; Krüger, Rejko UL; Amoiridis, G. et al

in Journal of neurology, neurosurgery, and psychiatry (1998), 64(1), 67-73

OBJECTIVE: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide ... [more ▼]

OBJECTIVE: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide repeat in the gene coding for the alpha1A-subunit of the voltage dependent calcium channel. The aim was to further characterise the SCA6 phenotype METHODS: The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadic cerebellar ataxia and the CAG repeat length of the expanded allele was correlated with the disease phenotype. RESULTS: Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Disease onset ranged from 30 to 71 years of age and was significantly later than in other forms of ADCA. Age at onset correlated inversely with repeat length. The SCA6 phenotype comprises predominantly cerebellar signs in concordance with isolated cerebellar atrophy on MRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAG repeat length. CONCLUSIONS: This study provides the first detailed characterisation of the SCA6 phenotype. Clinical features apart from cerebellar signs were highly variable in patients with SCA6. By comparison with SCA1, SCA2, and SCA3 no clinical or electrophysiological finding was specific for SCA6. Therefore, the molecular defect cannot be predicted from clinical investigations. In Germany, SCA6 accounts for about 13% of families with ADCA. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing is therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia. [less ▲]

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See detailAla30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.
Krüger, Rejko UL; Kuhn, W.; Muller, T. et al

in Nature genetics (1998), 18(2), 106-8

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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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See detailSelegiline stimulates biosynthesis of cytokines interleukin-1 beta and interleukin-6.
Wilfried, K.; Muller, T.; Krüger, Rejko UL et al

in Neuroreport (1996), 7(18), 2847-8

Several lines of evidence indicate an immune-mediated pathophysiology of Parkinson's disease (PD) and Alzheimer's disease (AD). In clinical studies the monoamine oxidase-B inhibitor Selegiline appears to ... [more ▼]

Several lines of evidence indicate an immune-mediated pathophysiology of Parkinson's disease (PD) and Alzheimer's disease (AD). In clinical studies the monoamine oxidase-B inhibitor Selegiline appears to slow the progression of neurological deficits in PD and the cognitive decline in AD. The immune response to bacterial or viral infection and in chronic inflammatory processes is stimulated by an increased synthesis of the cytokines interleukin-1 beta (IL-1 beta) and subsequently interleukin-6 (IL-6). We investigated the influence of Selegiline on the synthesis of IL-1 beta and IL-6 in peripheral blood mononuclear cells (PBMC) from healthy blood donors cultured with or without Selegiline (10(-8)M, 10(-9)M or 10(-10)M) in a humidified atmosphere (7% CO2). Treatment of cultured PBMC with Selegiline significantly increased synthesis of both cytokines. The effect of Selegiline on cytokine biosynthesis may contribute to its putative neuroprotective properties. [less ▲]

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