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Ullrich Wüllner

Publications and source records attributed to Ullrich Wüllner.

31 records · Page 2Linked to original sources
PubMed2004

Lack of association between the interleukin-1 alpha (-889) polymorphism and early-onset Parkinson's disease.

An increasing number of studies have shown that an inflammatory process is part of Parkinson's disease (PD) brain pathology. Interleukin-1 (IL-1) is a multifunctional cytokine and is considered to contribute to several inflammatory diseases. Recently, we detected an associated risk in a subgroup of PD patients with a disease onset < 50 years and a C to T transition in the IL-1alpha promoter (-889). One-hundred-seventy-six German PD patients (42.1 +/- 6.4 years; 42.4% male) and 170 unrelated age-matched control individuals (40.4 +/- 8.7 years; 57.6% male) were investigated for the presence of the IL-1alpha (-889C/T) polymorphism. No significant difference in the allelic distribution of the analyzed IL-1alpha polymorphism has been found between PD and controls. We conclude that the C/T polymorphism in the IL-1alpha promoter region at -889 does not increase the risk to develop PD.

Adult↗
PubMed2004

Antiparkinsonian activity of Ro 25-6981, a NR2B subunit specific NMDA receptor antagonist, in animal models of Parkinson's disease.

N-methyl-D-aspartate (NMDA) receptor antagonists have antiakinetic and antidyskinetic effects in animals models of Parkinson's disease (PD). However, non-selective inhibition of NMDA receptors throughout the central nervous system may result in undesired effects such as ataxia and psychosis. We therefore studied Ro 25-6981, an activity-dependent antagonist of NMDA receptors containing the NR2B subunit which are predominantly expressed in the striatum. Ro 25-6981 induced contraversive rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats without stimulating locomotion in normal rats and reversed parkinsonian symptoms in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-treated common marmosets. Due to the small number of marmosets, there were no significant differences between Ro 25-6981 and vehicle though there was a significant trend toward differences, as shown by the Page test. Furthermore, Ro 25-6981 potentiated the action of levodopa in both species and attenuated the maximal levodopa response in 6-OHDA-lesioned rats chronically treated with levodopa without reducing the overall response. Ro 25-6981 also potentiated the action of the dopamine receptor agonists apomorphine, A68930 and quinpirole in 6-OHDA-lesioned rats. The present observations suggest a therapeutic potential of NR2B-selective NMDA receptor antagonists in the management of PD.

Animals↗
PubMed2004

Structural and functional analysis of ataxin-2 and ataxin-3.

Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3) are autosomal-dominantly inherited, neurodegenerative diseases caused by CAG repeat expansions in the coding regions of the genes encoding ataxin-2 and ataxin-3, respectively. To provide a rationale for further functional experiments, we explored the protein architectures of ataxin-2 and ataxin-3. Using structure-based multiple sequence alignments of homologous proteins, we investigated domains, sequence motifs, and interaction partners. Our analyses focused on presumably functional amino acids and the construction of tertiary structure models of the RNA-binding Lsm domain of ataxin-2 and the deubiquitinating Josephin domain of ataxin-3. We also speculate about distant evolutionary relationships of ubiquitin-binding UIM, GAT, UBA and CUE domains and helical ANTH and UBX domain extensions.

Amino Acid Sequence↗
PubMed2003

Gene dosage-dependent effects of bcl-2 expression on cellular survival and redox status.

The human oncogene bcl-2 exerts protective functions in numerous models of apoptotic cell death and increased oxidative stress. We investigated the effects of inducible bcl-2 overexpression on cellular survival and redox status in dopaminergic rat pheochromocytoma PC 12 cells. Induction of high-level expression of bcl-2 in PC 12 cells resulted in generation of oxidative stress and cessation of growth by cell cycle arrest. Cell cycle arrest in bcl-2-overexpressing PC 12 cells was prevented by an inhibitor of extracellular signal-related kinase (ERK 1/2) activation. Protective effects of bcl-2 expression against L-DOPA neurotoxicity decreased with increasing amounts of bcl-2. Furthermore, high-level bcl-2 overexpression sensitized cells towards oxidative stress and glutathione depletion. Our data suggest that bcl-2 expression is beneficial only in a limited gene dosage range and that high-level expression of bcl-2 exerts potential deleterious effects.

Animals↗
PubMed2003

Structural modeling of ataxin-3 reveals distant homology to adaptins.

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3, a protein of yet unknown function. Based on a comprehensive computational analysis, we propose a structural model and structure-based functions for ataxin-3. Our predictive strategy comprises the compilation of multiple sequence and structure alignments of carefully selected proteins related to ataxin-3. These alignments are consistent with additional information on sequence motifs, secondary structure, and domain architectures. The application of complementary methods revealed the homology of ataxin-3 to ENTH and VHS domain proteins involved in membrane trafficking and regulatory adaptor functions. We modeled the structure of ataxin-3 using the adaptin AP180 as a template and assessed the reliability of the model by comparison with known sequence and structural features. We could further infer potential functions of ataxin-3 in agreement with known experimental data. Our database searches also identified an as yet uncharacterized family of proteins, which we named josephins because of their pronounced homology to the Josephin domain of ataxin-3.

Adaptor Protein Complex gamma Subunits↗
PubMed2003

In vivo voxel-based morphometry in multiple system atrophy of the cerebellar type.

BACKGROUND: Multiple system atrophy (MSA) is a sporadic neurodegenerative disease. According to the clinical presentation a parkinsonian type and a cerebellar type (MSA-C) are distinguished. OBJECTIVE: To study the morphological alterations of MSA-C-affected brains in vivo using voxel-based morphometric analysis of magnetic resonance images. SETTING: University hospital. PATIENTS: Fourteen patients (5 men and 9 women) with MSA-C (mean age [SD], 59.4 [7.4] years; mean [SD] disease duration, 3.7 [1.4] years) and 13 healthy control subjects (5 men and 8 women) (mean [SD] age, 55.1 [6.9] years) were studied. METHODS: T1-weighted magnetic resonance images were normalized to a common stereotaxic space and segmented into gray and white matter. Data were analyzed using statistical parametric mapping (SPM99). RESULTS: Gray matter was reduced in the brainstem and the anterior lobe of the cerebellum. Reduction of white matter was observed in the middle cerebellar peduncles, cerebellar white matter, and brainstem. The inverted comparison revealed an increase of white matter density along the pyramidal tracts. CONCLUSIONS: Voxel-based morphometry revealed a significant loss of cerebellar and brainstem tissue in MSA-C. It allowed a precise anatomical localization and a distinction between gray and white matter densities. In addition, our data point to a particular involvement of the pyramidal tract in MSA-C.

Brain Stem↗
PubMed2003

Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson's disease.

To study the putative association of dopamine agonists with sleep attacks in patients with Parkinson's disease (PD) and their relation to daytime sleepiness, we performed a survey of 2,952 PD patients in two German counties. In 177 patients, sudden, unexpected, and irresistible sleep episodes while engaged in some activity were identified in a structured telephone interview. Ninety-one of these patients denied the occurrence of appropriate warning signs. A total of 133 patients (75%) had an Epworth Sleepiness Scale (ESS) score >10; 65 (37%) >15. Thirty-one patients (18%) had an ESS score < or =10 and yet experienced sleep attacks without warning signs. Thus, although a significant proportion of patients at risk for sleep attacks might be identified using the ESS, roughly 1% of the PD patient population seems to be at risk for sleep attacks without appropriate warning signs and without accompanying daytime sleepiness. Sleep attacks occurred with all dopamine agonists marketed in Germany (alpha-dihydroergocryptine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole), and no significant difference between ergot and nonergot drugs was evident. Levodopa (L-dopa) monotherapy carried the lowest risk for sleep attacks (2.9%; 95% confidence interval [CI], 1.7-4.0%) followed by dopamine agonist monotherapy (5.3%; 95% CI, 1.5-9.2%) and combination of L-dopa and a dopamine agonist (7.3%; 95% CI, 6.1-8.5%). Neither selegeline nor amantadine or entacapone appeared to influence the occurrence of sleep attacks. A high ESS score, intake of dopamine agonists, and duration of PD were the main influencing factors for the occurrence of sleep attacks. The odds ratio for dopamine agonist therapy was 2.9 compared to 1.9 with L-dopa therapy and 1.05 for a 1-year-longer disease duration.

Activities of Daily Living↗
PubMed2003

Olfactory dysfunction in cerebellar ataxia and multiple system atrophy.

BACKGROUND: Olfactory dysfunction has been reported in Parkinson's (PD) and Alzheimer's disease (AD). OBJECTIVE: We studied olfactory function in eight patients with multiple system atrophy of cerebellar type (MSA-C), eleven patients with sporadic cerebellar ataxia of unknown etiology and thirteen controls matched for age and gender. Subjects received tests for n-butanol odor thresholds, odor identification, and odor discrimination. RESULTS: Olfactory thresholds were abnormally high in 16% of the patients. Odor discrimination and odor identification were impaired in 44 % and 74% of the patients, respectively. There was no significant difference in olfactory function between patients with sporadic ataxia of unknown etiology and MSA-C patients. CONCLUSIONS: The present data suggest that olfactory dysfunction is common to various neurodegenerative disorders and not specifically restricted to PD or AD. Cerebellar dysfunction affected suprathreshold olfactory function more severely than odor thresholds. Thus cerebellar lesions may affect the processing of odor-related information to a higher degree than the transport of odorants to the receptor through sniffing.

Cerebellar Ataxia↗
PubMed2003

Gene expression profiling in ataxin-3 expressing cell lines reveals distinct effects of normal and mutant ataxin-3.

Spinocerebellar ataxia type 3 (SCA3) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the gene product, ataxin-3. We have previously shown that mutant ataxin-3 causes upregulation of inflammatory genes in transgenic SCA3 cell lines and human SCA3 pontine neurons. We report here a complex pattern of transcriptional changes by microarray gene expression profiling and Northern blot analysis in a SCA3 cell model. Twenty-three differentially expressed genes involved in inflammatory reactions, nuclear transcription, and cell surface-associated processes were identified. The identified corresponding proteins were analyzed by immunohistochemistry in human disease and control brain tissue to evaluate their implication in SCA3 pathogenesis. In addition to several inflammatory mediators upregulated in mutant ataxin-3 expressing cell lines and pontine neurons of SCA3 patients, we identified a profound repression of genes encoding cell surface-associated proteins in cells overexpressing normal ataxin-3. Correspondingly, these genes were upregulated in mutant ataxin-3 expressing cell lines and in pontine neurons of SCA3 patients. These findings identify for the first time target genes transcriptionally regulated by normal ataxin-3 and support the hypothesis that both loss of normal ataxin-3 and gain of function through protein-protein interacting properties of mutant ataxin-3 contribute to SCA3 pathogenesis.

Animals↗
PubMed2003

Genes implicated in the pathogenesis of spinocerebellar ataxias.

The degenerative ataxias comprise a number of heterogeneous diseases, many of which are genetically determined. Loss of cerebellar Purkinje and brainstem neurons as well as degeneration of spinal pathways are the major morphological findings of most ataxias, but neuronal loss may also affect the basal ganglia and the retina. While the degenerative ataxias initially were classified on a neuropathological basis, more recent classifications focused on clinical hallmarks and the mode of inheritance, separating inherited, sporadic and symptomatic ataxias. Genetic linkage analysis and molecular genetic studies identified various genotypes and revealed genetic heterogeneity of the autosomal dominant ataxias (ADCA), which on the basis of the genotypes are now classified as spinocerebellar ataxias (SCA1-22). Based on pathogenesis these disorders fall into three discrete groups: the polyglutamine disorders, SCA1-3, 7 and 17; the channelopathies, SCA6 and episodic ataxia types 1 and 2 (EA1-2); and SCA8, 10 and 12, which result from repeat expansions outside the coding regions and reduce gene expression. The etiologies of SCAs 4, 5, 9, 11, 13-16, 19, 21 and 22 remain unknown as of today. The recent advances in the identification of the underlying gene defects of most of the inherited ataxias have opened new avenues to a better understanding of the molecular mechanisms leading to cellular dysfunction and cell death.

Drug Therapy↗
PubMed2002

Bcl-2 up-regulates ha-ras mRNA expression and induces c-Jun phosphorylation at Ser73 via an ERK-dependent pathway in PC 12 cells.

Members of the Bcl-2 family of proteins function either to promote or to repress apoptosis. Bcl-2 has been mainly localised to the mitochondria and acts predominantly upstream of cytochrome c release in its prevention of apoptosis. Little is known about the function of Bcl-2 independent of an apoptotic stimulus. Here we demonstrate that inducible overexpression of the anti-apoptotic protein Bcl-2 in a PC12 Tet-on- cell line up-regulates mRNA expression and leads to phosphorylation of c-Jun at Ser73 via the ERK pathway in a time and concentration dependent manner. Phosphorylation of c-Jun was inhibited by the addition of the selective ERK inhibitor PD 98059. No activation of the stress-activated protein kinases JNK and p38 could be detected. This is the first evidence of a direct activation of the Ras-Raf-MAPK cascade by an anti-apoptotic protein. We propose that the selective activation of Ras, the ERK pathway and the subsequent phosphorylation of c-Jun contribute to the anti-apoptotic action of Bcl-2.

Animals↗