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Biomedical subjects

T Klockgether

Publications and source records attributed to T Klockgether.

At least 127 records · Page 7Linked to original sources
PubMed1998

The natural history of degenerative ataxia: a retrospective study in 466 patients.

The aim of the present study was (i) to compare disease progression and survival in different types of degenerative ataxia, and (ii) to identify variables that may modify the rate of disease progression. We included patients suffering from Friedreich's ataxia (FRDA, n = 83), early onset cerebellar ataxia (EOCA, n = 30), autosomal dominant cerebellar ataxia (ADCA) type I (ADCA-I, n = 273), ADCA-III (n = 13) and multiple system atrophy (MSA, n = 67). Molecular genetic testing allowed us to assign 202 ADCA-I patients to one of the following subgroups: spinocerebellar ataxia type I (SCAI, n = 36), SCA2 (n = 56) and SCA3 (n = 110). To assess disease progression we defined the following disease stages: stage 0 = no gait difficulties; stage 1 = disease onset, as defined by onset of gait difficulties; stage 2 = loss of independent gait; stage 3 = confinement to wheelchair; stage 4 = death. Disease progression was most rapid in MSA, intermediate in FRDA, ADCA-I and ADCA-III and slowest in EOCA. The rate of progression was similar in SCA1, SCA2 and SCA3. The CAG repeat length was a significant risk factor for faster progression in SCA2 and SCA3, but not in SCA1. In FRDA, the time until confinement to wheelchair was shorter in patients with earlier disease onset, suggesting that patients with long GAA repeats and early disease onset have a poor prognosis. Female gender increased the risk of becoming dependent on walking aids or a wheelchair, but it did not influence survival in FRDA, SCA3 and MSA. In SCA2, female gender was associated with shortened survival. In MSA, later age of onset increased the risk of rapid progression and death.

Adolescent↗
PubMed1998

Autosomal dominant cerebellar ataxia type I. MRI-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types 1, 2 and 3.

Twenty-six patients suffering from autosomal dominant cerebellar ataxia type I were subjected to a genotype-phenotype correlation analysis using molecular genetic assignment to the genetic loci for spinocerebellar ataxia type 1, 2 or 3 (SCA1, SCA2, SCA3) and MRI-based volumetry of posterior fossa structures and basal ganglia nuclei. There was significant atrophy of the cerebellum and brainstem in all three SCA mutations compared with a group of 31 age- and sex-matched controls. Comparison between the SCA groups showed that cerebellar and brainstem atrophy was more severe in SCA2 than in SCA1 and SCA3. Putaminal and caudate volume was reduced only in SCA3, but not in SCA1 and SCA2. A set of three morphological criteria was defined that enabled us to assign all SCA2 and SCA3 patients correctly to the underlying genotype. In contrast, these criteria did not distinguish SCA1 from SCA2 and SCA3. Regression analysis failed to reveal a significant association between CAG repeat length and the volumes of the respective brain structures in any of the SCA mutant types. The present data provide in vivo evidence that SCA2 and SCA3 lead to distinct patterns of brain atrophy, while the atrophy changes in SCA1 overlap with both SCA2 and SCA3.

Adult↗
PubMed1998

An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients.

Autosomal dominant spinocerebellar ataxias (SCA) form a group of clinically and genetically heterogeneous neurodegenerative disorders. The defect responsible for SCA3/Machado-Joseph disease (MJD) has been identified as an unstable and expanded (CAG)n trinucleotide repeat in the coding region of a novel gene of unknown function. The MJD1 gene product, ataxin-3, exists in several isoforms. We generated polyclonal antisera against an alternate carboxy terminus of ataxin-3. This isoform, ataxin-3c, is expressed as a protein of approximately 42 kDa in normal individuals but is significantly enlarged in affected patients confirming that the CAG repeat is part of the ataxin-3c isoform and is translated into a polyglutamine stretch, a feature common to all known CAG repeat disorders. Ataxin-3 like immunoreactivity was observed in all human brain regions and peripheral organs studied. In neuronal cells of control individuals, ataxin-3c was expressed cytoplasmatically and had a somatodendritic and axonal distribution. In SCA3 patients, however, C-terminal ataxin-3c antibodies as well as anti-ataxin-3 monoclonal antibodies (1 H9) and anti-ubiquitin antibodies detected intranuclear inclusions (NIs) in neuronal cells of affected brain regions. A monoclonal antibody, 2B6, directed against an internal part of the protein, barely detected these NIs implying proteolytic cleavage of ataxin-3 prior to its transport into the nucleus. These findings provide evidence that the alternate isoform of ataxin-3 is involved in the pathogenesis of SCA3/MJD. Intranuclear protein aggregates appear as a common feature of neurodegenerative polyglutamine disorders.

Amino Acid Sequence↗
PubMed1998

Potassium deprivation-induced apoptosis of cerebellar granule neurons: cytochrome c release in the absence of altered expression of Bcl-2 family proteins.

Bcl-2 family proteins are principal regulators of cell death during normal development as well as in many disease states. Differentiated cerebellar granule neurons are protected from apoptosis by depolarizing concentrations of potassium. Further, these cells acquire resistance to glutamate-mediated excitotoxicity when pre-exposed to subtoxic concentrations of the glutamate receptor agonist, N-methyl-D-aspartate. Here, we report that the expression of bcl-2, bcl-xL, bcl-xS, bax and bad mRNA as well as of Bcl-2, Bax, Bcl-XL, Bcl-XS and Bag-1 proteins is not modulated in these two paradigms of neuronal cell death. However, mitochondrial release of cytochrome c, which is thought to be controlled by Bcl-2 family proteins, is detected 5 h after switching the neurons to low potassium conditions. Thus, there appears to be regulation of Bcl-2 family protein bioactivity in the absence of altered protein expression during potassium deprivation-induced apoptosis of cerebellar granule neurons.

Animals↗
PubMed1998

Mechanisms of cell death in cerebellar disorders.

Recent advances in molecular genetic and cellular biology have provided new insights into the mechanisms leading to neuronal dysfunction and cell death in the disorders of the cerebellum. Trinucleotide repeat expansions have been identified as an important cause of inherited cerebellar ataxias and mechanisms involved in apoptotic cell death have become centerstage of scientific interest. In the present article, we review the recent findings in trinucleotide repeat disorders and address the possible link of glutamate neurotoxicity, impaired Ca2+ homeostasis and apoptosis.

Journal Article↗
PubMed1997

The NMDA antagonist memantine impairs classical eyeblink conditioning in humans.

The present study investigated the effects of a single oral dose (30 mg) of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist memantine on memory and learning in human subjects. Sixteen male healthy volunteers participated in a double blind placebo controlled study. There were no significant effects of memantine on mood, attention or immediate and delayed verbal and visuospatial memory. Memantine did, however, delay the acquisition of classical eyeblink conditioning and reduced the overall frequency of conditioned responses without affecting reflex or spontaneous eyeblinks. These findings are compatible with the higher affinity of memantine to cerebellar as compared to forebrain tissue and demonstrate the dissociability of different memory systems by pharmacological tools.

Adult↗
PubMed1997

Differential interaction of competitive NMDA and AMPA antagonists with selective dopamine D-1 and D-2 agonists in a rat model of Parkinson's disease.

Stimulation of the dopamine (DA) D-2 and D-1 receptors results in behavioural activation (i.e., induction of contralateral rotations) in 6-hydroxydopamine (6-OHDA) substantia nigra lesioned rats. Competitive N-methyl-D-aspartate (NMDA) antagonists as well as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists potentiate the stimulatory responses to threshold doses of L-DOPA or the mixed dopamine D-1/D-2 agonist apomorphine in this model, indicating the potential of such combinations for the management of Parkinson's disease. Neuroanatomic and electrophysiologic data indicate a differential distribution of DA D-1 and DA D-2 receptors within motor loops of the basal ganglia. DA D-1 receptors are preferentially located on GABAergic neurones projecting to the substantia nigra compacta (SNc) and to the substantia nigra reticulata (SNr), whereas DA D-2 receptors are preferentially located on neurones that innervate the external pallidum. NMDA receptors are present in high densities within the striatum, whereas AMPA receptors are enriched in the entopeduncular nucleus/internal pallidum and the SNr. To further characterise the functional interaction between DA and glutamate receptors, we tested the competitive NMDA antagonist 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f] quinoxaline (NBQX) following systemic administration in combination with the DA D-2 selective agonist quinpirole or the DAD-1 selective agonist A 68 930 (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman) in rats with chronic 6-OHDA lesions of the SNc. CPP potentiated quinpirole-induced rotations and did not affect those induced by the D-1 agonist A 68930. By contrast, NBQX had no effect on quinpirole-induced rotations, whereas synergism was seen with A 68930. These results suggest that rotations induced by combined treatment with glutamate antagonists and DA agonists are mediated by different pathways within the basal ganglia, depending on which subtype of receptor is involved. AMPA antagonists could act preferentially by activating the direct motor pathway, whereas NMDA antagonists could modulate the indirect loop.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Developmental and genetic regulation of programmed neuronal death.

Apoptotic neuronal death is a key mechanism that regulates the elimination of neuronal precursor cells during the development of the mammalian brain. The principal action of neurotrophins such as nerve growth factor is probably the suppression of the preexistent machinery of programmed cell death that is readily activated in neurons deprived of neurotrophins. Potassium-mediated neuronal depolarization prolongs neuronal survival in vitro and has become a major model of examining neuronal apoptosis. Apoptosis induced by potassium deprivation triggers a lethal cascade of events that includes specific RNA and protein synthesis, induction of interleukin 1-converting enzyme-like protease activity, and generation of free radicals. Neuronal susceptibility to apoptosis is also regulated by the expression of bcl-2 family proteins. Current research focuses on the significance of these findings for the premature death of adult neurons in human neurodegenerative diseases.

Adult↗
PubMed1997

Clinical and genetic analysis of three German kindreds with autosomal dominant cerebellar ataxia type I linked to the SCA2 locus.

The detailed clinical, electrophysiological and imaging data of three German autosomal dominant cerebellar ataxia (ADCA) families are reported. Linkage to SCA2 was established using microsatellite markers D12S105, D12S1339(1328), D12S1304(1329) yielding a lod score exceeding +3.0 for the combined data. Analysis of the pedigree data provided evidence of anticipation as observed in other neurodegenerative disorders due to polyglutamine expansion encoded by a CAG repeat. This hypothesis was confirmed by the detection of the SCA2-specific pathological protein using the 1C2 monoclonal antibody which selectively recognizes large polyglutamine expansions and the characterization of a CAG expansion in the patients. Clinically, the families were characterized by progressive ataxia of stance, gait and limbs. Saccade velocity was markedly reduced in SCA2. Further oculomotor findings were gaze palsy, impaired smooth pursuit and reduced optokinetic reflex. Dementia and pyramidal tract signs were rather rare, while peripheral involvement (reduced or absent ankle reflexes, fasciculation-like movements, amyotrophy) was a prominent feature. Electrophysiological investigations provided evidence of sensory neuropathy of the axonal type and degeneration of the posterior columns. Imaging studies demonstrated severe shrinkage of brain-stem structures even in early stages of the disease.

Adult↗
PubMed1997

Locus heterogeneity in Friedreich ataxia.

Friedreich ataxia (FRDA) is the most common form of autosomal recessive ataxia. The disease locus was assigned to chromosome 9 and the disease gene, STM7/X25, has been isolated. To date most data suggest locus homogeneity in FRDA. We now provide strong evidence of a second FRDA locus. Studying two siblings with FRDA from two families we did not detect a mutation in STM7/X25. Haplotype analysis of the STM7/X25 region of chromosome 9 demonstrated that the relevant portion of chromosome 9 differs in the patients. Although the patients studied had typical FRDA, one sibpair had the uncommon symptom of retained tendon reflexes. In order to investigate whether retained tendon reflexes are characteristic of FRDA caused by the second locus, FRDA2, we studied an unrelated FRDA patient with retained tendon reflexes. The observation of typical mutations in STM7/X25 (GAA expansions) in this patient demonstrates that the two genetically different forms of FRDA cannot be distinguished clinically.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Evidence for an active type of cell death with ultrastructural features distinct from apoptosis: the effects of 3-acetylpyridine neurotoxicity.

3-Acetylpyridine is a niacinamide antagonist with potent neurotoxic properties in vitro and in vivo. 3-Acetylpyridine neurotoxicity was associated with positive DNA end-labelling and displayed features of active cell death without the ultrastructural changes of apoptotic cell death. After systemic administration in rats (70 mg/kg), we detected labelled nuclei in the inferior olive using in situ DNA end-labelling. However, the conventional chromatin stain did not show chromatin condensation or fragmentation and electron microscopy studies failed to reveal features of apoptosis. Although areas of condensed chromatin were present in some nuclei, cytoplasmic damage with extensive organelle swelling was the most prominent finding. In vitro, 3-acetylpyridine (0.1-1 mM) induced degeneration of cerebellar granule neurons in a concentration- and time-dependent manner. The protein synthesis inhibitor cycloheximide (10 micrograms/ml) and the transcriptional inhibitor actinomycin D (10 microM) protected against 3-acetylpyridine toxicity. In contrast, neither the free radical scavenger alpha-phenyl-N-tertbutylnitron (100 microM), nor glutathione ethyl ester (10-100 microM), N-acetyl-cysteine (10-200 microM) or 3-aminobenzamide (0.1-4 mM), an inhibitor of poly(ADP-ribose) synthesis, were effective. 3-Acetylpyridine-induced neuronal death in vitro was associated with positive in situ DNA labelling. However, DNA fragmentation could not be demonstrated prior to neuronal cell loss and no DNA "laddering" was detected by DNA gel electrophoresis. Correspondingly, no apoptotic nuclei were revealed upon electron microscopy but organelle swelling and extensive vacuolization, changes similar to autophagocytosis. In conclusion, 3-acetylpyridine induces an active form of cell death that required de novo protein synthesis but is distinct from apoptosis. A loss of glutathione accompanies, but does not precede, cell death.

Animals↗
PubMed1997

Cooperative interception of neuronal apoptosis by BCL-2 and BAG-1 expression: prevention of caspase activation and reduced production of reactive oxygen species.

Neuronally differentiated PC12 cells undergo synchronous apoptosis when deprived of nerve growth factor (NGF). Here we show that NGF withdrawal induces actinomycin D- and cycloheximide-sensitive caspase (ICE-like) activity. The peptide inhibitor of caspase activity, N-acetyl-Asp-Glu-Val-Asp-aldehyde, was more potent than acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone in preventing NGF withdrawal-induced apoptosis, suggesting an important role for caspase-3 (CPP32)-like proteases. We observed a peak of reactive oxygen species (ROS) 6 h after NGF withdrawal. ROS appear to be required for apoptosis, because cell death is prevented by the free radical spin trap, N-tert-butyl-alpha-phenylnitrone, and the antioxidant, N-acetylcysteine. ROS production was blocked by actinomycin D, cycloheximide, and caspase protease inhibitors, suggesting that ROS generation is downstream of new mRNA and protein synthesis and activation of caspases. Forced expression of either BCL-2 or the BCL-2-binding protein BAG-1 blocked NGF withdrawal-induced apoptosis, activation of caspases, and ROS generation, showing that they function upstream of caspases. Coexpression of BCL-2 and BAG-1 was more protective than expression of either protein alone.

Animals↗
PubMed1997

Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3.

Forty-one patients suffering from autosomal dominant cerebellar ataxia type I (ADCA-I) were subjected to a genotype-phenotype correlation analysis using molecular genetic assignment to the spinocerebellar ataxia type 1, 2 or 3 (SCA1, -2 or -3) genetic locus, clinical examination and nerve conduction as well as evoked potential studies. Pyramidal tract signs, pale discs, and dysphagia were more frequent in SCA1 compared with SCA2 and SCA3 patients, while double vision occurred less frequently. Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation were abnormal in almost all SCA1 patients, but only in a minority of SCA2 and SCA3 patients. In contrast, somatosensory evoked potentials were delayed or absent in the majority of patients with no significant differences between the mutations. Abnormalities of brainstem auditory evoked potentials were found in about half of the patients irrespective of the underlying mutation. In addition, reduced sensory nerve action potentials, suggesting sensory axonal neuropathy were found in all three mutations. These findings provide electrophysiological evidence that pyramidal and visual pathways are differentially affected in SCA1, SCA2 and SCA3 patients.

Action Potentials↗
PubMed1997

Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families.

Spinocerebellar ataxia 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. One hundred and eighty four index patients with autosomal dominant cerebellar ataxia type I were screened for this mutation. We found expansion in 109 patients from 30 families of different geographical origins (15%) and in two isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14-31 repeats), except one with 14 repeats, were interrupted by 1-3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat (r = -0.81). The frequency of several clinical signs such as myoclonus, dystonia and myokymia increased with the number of CAG repeats whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of one patient.

Adolescent↗
PubMed1997

SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene.

Recently, moderate (CAG)>20 repeat expansions in the alpha1A-voltage-dependent calcium channel gene (CACNL1A4) have been identified in a previously unmapped type of SCA which has been named SCA6. We investigated the (CAG)n repeat length of the CACNL1A4 gene in 733 patients with sporadic ataxia and in 46 German families with dominantly inherited SCA which do not harbor the SCA1, SCA2, or MJD1/SCA3 mutation, respectively. The SCA6 (CAG)n expansion was identified in 32 patients most frequently with late manifestation of the disease. The (CAG)n stretch of the affected allele varied between 22 and 28 trinucleotide units and is therefore the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. The (CAG)n repeat length is inversely correlated with the age at onset. In 11 parental transmissions of the expanded allele no repeat instability has been observed. Repeat instability was also not found for the normal allele investigating 431 meioses in the CEPH families. Analyzing 248 apparently healthy octogenerians revealed one allele of 18 repeats which is the longest normal CAG repeat in the CACNL1A4 gene reported. The SCA6 mutation causes the disease in approximately 10% of autosomal dominant SCA in Germany. Most importantly, the trinucleotide expansion was observed in four ataxia patients without obvious family history of the disease which necessitates a search for the SCA6 (CAG)n expansion even in sporadic patients.

Age of Onset↗