Search Results - (Author, Cooperation:T. Klockgether)

2011-11-25

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Ataxin-3 ; Calcium/metabolism ; Calpain/metabolism ; Cells, Cultured ; Excitatory Amino Acids/pharmacology ; Glutamic Acid/pharmacology ; Humans ; Machado-Joseph Disease/*pathology ; Nerve Tissue Proteins/*metabolism ; Neurons/drug effects/*metabolism ; Nuclear Proteins/*metabolism ; Repressor Proteins/*metabolism

1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract : The inhibitor of apoptosis (IAP) family of anti-apoptoticgenes, originally discovered in baculovirus, exists in animals ranging frominsects to humans. Here, we investigated the ability of IAPs to suppress celldeath in both a neuronal model of apoptosis and excitotoxicity. Cerebellargranule neurons undergo apoptosis when switched from 25 to 5 mMpotassium, and excitotoxic cell death in response to glutamate. We examinedthe endogenous expression of four members of the IAP family, Xchromosome-linked IAP (XIAP), rat IAP1 (RIAP1), RIAP2, and neuronal apoptosisinhibitory protein (NAIP), by semiquantitative reverse PCR and immunoblotanalysis in cultured cerebellar granule neurons. Cerebellar granule neuronsexpress significant levels of RIAP2 mRNA and protein, but expression of RIAP1,NAIP, and XIAP was not detected. RIAP2 mRNA content and protein levels did notchange when cells were switched from 25 to 5 mM potassium. Todetermine whether ectopic expression of IAP influenced neuronal survival afterpotassium withdrawal or glutamate exposure, we used recombinant adenoviralvectors to target XIAP, human IAP1 (HIAP1), HIAP2, and NAIP into cerebellargranule neurons. We demonstrate that forced expression of IAPs efficientlyblocked potassium withdrawal-inducedN-acetly-Asp-Glu-Val-Asp-specific caspase activity and reduced DNAfragmentation. However, neurons were only protected from apoptosis up to 24 hafter potassium withdrawal, not at later time points suggesting that IAPSdelay but do not block apoptosis in cerebellar granule neurons. In contrast,treatment with 100 μM or 1 mM glutamate did not induce caspase activity and adenoviral-mediated expression of IAPs had no influence on subsequent excitotoxic cell death.

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1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Inhibitor-of-differentiation 2 (Id2) belongs to a family of transcriptional modulators that are characterized by a helix loop helix region but lack the basic amino acid domain. During development, Id2 antagonizes differentiation mediated by the retinoblastoma protein, probably by scavenging downstream E-box basic helix-loop-helix proteins. Here, using differential display RT-PCR, we identify Id2 as an induced gene during serum and potassium deprivation-induced apoptosis of cerebellar granule neurons. Consistent with a biological role for induced Id2 messenger RNA and protein expression in neuronal cell death, expression of Id2 antisense RNA, or targeted deletion of the Id2 gene in neurons from Id2 knock-out mice, protect from apoptosis. Further, gene transfer- mediated overexpression of Id2 induces neuronal cell death both in high potassium and low potassium conditions. Thus, the present study defines a role for Id2 in the modulation of neuronal apoptosis.

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1546-170X

Nature Archives 1869 - 2009

Biology

Medicine

[Auszug] THE HEREDITARY ATAXIAS COMPRISE a heterogeneous group of neurodegen-erative disorders with progressive ataxia as the primary symptom. They can be divided into autosomal dominant disorders such as the spinocerebellar ataxias (SCA), and autosomal recessive disorders, the most common of which is ...

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1546-1718

Nature Archives 1869 - 2009

Biology

Medicine

[Auszug] The autosomal dominant cerebellar ataxias (ADCA) are a group of neurodegenerative disorders characterized by onset with gait ataxia, dysarthria, dysmetria and dysdiadochokinesia. We have demonstrated previously genetic heterogeneity within these disorders by excluding the disease locus from the ...

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1435-1463

Budipine ; NMDA receptor ; Parkinson's disease

Springer Online Journal Archives 1860-2000

Medicine

Summary Budipine (1-t-butyl-4,4-diphenylpiperidine) is a novel antiparkinsonian agent. Its clinical efficacy has been proven in double-blind placebo-controlled trials. The mechanism of action of budipine, however, is unknown. Budipine selectively increased the threshold of N-methyl-D-aspartate (NMDA)-induced seizures in mice. Similar to known specific NMDA antagonist, budipine depressed polysynaptic spinal reflexes in mice, but had no consistent effect on spinal monosynaptic reflexes. In receptor binding experiments, budipine displaced thienylcyclohexylpiperidyl-3,4-[3H]-(n) ([3H]-TCP) from its binding site with an IC50 of 36 μM suggesting that budipine acts as a non-competitive NMDA antagonist with moderate receptor affinity. It is concluded that the newly discovered NMDA antagonistic action of budipine is at least partly responsible for its antiparkinsonian activity. Our findings are additional evidence for the hypothesis that NMDA antagonists may be useful in the treatment of Parkinson's disease (PD).

Electronic Resource

1432-1459

Cerebellar encephalitis ; Epstein-Barr virus ; Varicella-zoster ; Magnetic resonance imaging

Springer Online Journal Archives 1860-2000

Medicine

Abstract We examined 11 adult patients with cerebellar encephalitis (CE) during the acute phase of the disease and at least 12 months later. Five patients were aged between 23 and 31 years, 3 patients between 43 and 44 years and 3 patients between 60 and 64 years. Serological tests gave evidence of Epstein-Barr virus infection in 4 of the 5 young patients. Two patients had serological evidence of varicella-zoster virus reactivation, whereas the serological findings were negative in all other cases. All patients in the younger and middle age groups recovered within 3–30 weeks after onset of CE. If at all, they had only minor cerebellar deficits at the follow-up examination. Magnetic resonance imaging (MRI) examination performed at the follow-up examination was normal in all of them. In contrast, 2 of 3 patients older than 60 years had persistent cerebellar ataxia following CE. In these patients, MRI revealed infratentorial atrophy. Our data show that the clinical spectrum of CE in adults is wider than assumed so far. In addition to typical cases of CE in young male patients with good recovery, CE may also occur in older patients and give rise to persistent cerebellar ataxia.

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1433-0407

Schlüsselwörter Trinukleotid-Repeat ; Autosomal dominante zerebelläre Ataxie ; Spinozerebelläre Ataxie ; Episodische Ataxie ; Friedreich-Ataxie ; Key words Trinucleotide repeat ; Autosomal dominant cerebellar ataxia ; Spinocerebellar ataxia ; Episodic ataxia ; Friedreich’s ataxiaFriedreich-Ataxie

Springer Online Journal Archives 1860-2000

Medicine

Summary The hereditary ataxias are a heterogeneous group of inherited neurodegenerative disorders characterised by progressive ataxia that results from degeneration of the cerebellum and its afferent and efferent connections. With respect to the pathogenic mechanisms, the hereditary ataxias may be tentatively divided into three groups: (1) The recessive ataxias are induced by the functional impairment of a protein that is essential for the survival of specific neurons while the autosomal dominant ataxias are either caused by (2) mutations of genes coding for ion channels thus resulting in a channelopathy or by (3) a novel deleterious function of a extended polyglutamine sequence within the proteins encoded by the respective genes.

Zusammenfassung In den letzten Jahren ermöglichte die Klonierung krankheitsverursachender Gene neue Einblicke in die Ätiologie und Pathogenese der hereditären Ataxien. Die den einzelnen Ataxie-Formen zugrundeliegenden Mutationen führen trotz struktureller Gemeinsamkeiten auf unterschiedlichem Wege zur Neurodegeneration. Im wesentlichen lassen sich 3 Pathomechanismen unterscheiden: 1. Bei den autosomal rezessiven Ataxien kommt es aufgrund des Mangels eines für das Überleben von Neuronen direkt oder indirekt essentiellen Proteins zu neuronalem Zelltod. Beispielhaft wird hier die rezessiv vererbte Friedreich-Ataxie (FRDA) erörtert, bei der aufgrund eines Mangels an Frataxin, einem mitochondrial lokalisierten Protein, eine unphysiologische Eisenakkumulation in den Mitochondrien und oxidativer Stress entstehen. Bei den autosomal dominant erblichen Ataxien wird der Krankheitsprozeß durch eine 2. Funktionsstörung von Ionenkanälen, eine Kanalerkrankung, oder eine 3. schädigende, bislang nicht endgültig definierte neu erworbene Funktion des veränderten Genproduktes hervorgerufen.

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1432-0533

Key words Parkinson’s disease ; Apoptosis ; Bcl-2 ; Bax ; Bcl-x

Springer Online Journal Archives 1860-2000

Medicine

Abstract We studied the substantia nigra of three Parkinson’s disease (PD) patients and three age-matched individuals by in situ DNA-end labeling (ISEL) and immunohistochemistry for the apoptosis regulating proteins Bcl-2, Bax and Bcl-x on 50 consecutive sections per patient. No melanin-containing cell was identified with typical apoptotic changes in either patient or control substantia nigra. With prolonged reaction-time the terminal transferase-mediated DNA-end labeling revealed a signal in 2.0 ± 1.2% melanin-containing cells in PD compared to 1.3 ± 1.1% in control. This difference did nor reach statistical significance and no condensation or margination of the chromatin was evident. No significant changes of any of the apoptosis regulating proteins were apparent in PD substantia nigra. These findings do not support the hypothesis that apoptosis plays a central role in the pathogenesis of PD.

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1432-0533

Key words  Apoptosis ; Bcl-2 ; Bax ; Bcl-x ; Cerebellum

Springer Online Journal Archives 1860-2000

Medicine

Abstract We investigated the expression of the apoptosis modulating proteins Bcl-2, Bax and Bcl-x in the cerebellum of mutant lurcher and weaver mice. Lurcher Purkinje cells and weaver germinal (granule neuron progenitor) cells both die via apoptosis during the postnatal cerebellar development. No significant changes in the expression patterns were detected prior to the actual cell death process. Instead apoptotic lurcher Purkinje cells exhibited increased Bax and Bcl-x expression, while surviving cells had an expression pattern similar to that of healthy littermates. Increased Bax expression was also found in apoptotic weaver germinal cells, while no change of Bcl-x expression was detected. Bcl-2 was expressed at low levels in cerebellar neurons and no loss of Bcl-2 was evident. The observed expression patterns of Bcl-2, Bax and Bcl-x protein in apoptotic lurcher and weaver neurons support the hypothesis that the execution of neuronal apoptosis involves increased expression of Bax, which could represent a general mechanism in diverse neurodegenerative processes.

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1432-1106

GABA ; Motor pattern ; Motor performance ; Substantia nigra

Springer Online Journal Archives 1860-2000

Medicine

Summary In order to investigate the role of GABAergic neurotransmission within the reticular part of substantia nigra (SNR) in the switching of motor patterns and the performance of movements, cats trained to walk on the running belt of a treadmill at constant speed were subjected to three different tests: (1) a food dispenser test measuring the animals' capacity to switch motor patterns in order to get access to food during walking; (2) an obstacle test measuring the animals' capacity to switch motor patterns in reaction to incoming obstacles; (3) EMG recording of two representative antagonistic muscles of the hindlimb during walking on the treadmill. Local injection of a moderate dose of the GABA antagonist picrotoxin (PTX; 250–500 ng/0.5 μl) into the SNR disrupted the animals' capacity to switch motor patterns in the food dispenser test, but not in the obstacle test. These animals displayed normal EMG patterns during walking. Higher doses of intranigral injections of PTX, however, impaired the execution of movements per se as detected by an increased number of ‘faults’ in the obstacle test and pathological EMG patterns during walking. These experiments support the view that (1) the SNR plays a distinct role for switching motor patterns; (2) the SNR is involved in the control of movements per se; (3) the degree of motor disorder depends on the degree of pathology within this brain structure.

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1432-1106

Catalepsy ; Dopamine ; Medial prefrontal cortex ; Neostriatum

Springer Online Journal Archives 1860-2000

Medicine

Summary To investigate the behavioural role of mesocortical dopamine innervation we performed bilateral microinjections of haloperidol into various parts of the rat frontal cortex and into adjacent subcortical forebrain structures. Haloperidol (2.5 μg/ 0.5 μl) locally injected into the medial prefrontal cortex or into the rostral part of the neostriatum resulted in the development of catalepsy as measured in the bar test. In contrast, injections of haloperidol into the nucleus accumbens, more caudal parts of the neostriatum, anterior cingulate cortex, rostral and lateral parts of the prefrontal cortex and into the lateral ventricles failed to induce catalepsy. It is concluded that blockade of dopamine receptors located in the rostral neostriatum and in the medial prefrontal cortex contributes to the development of haloperidol induced catalepsy.

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1432-1106

δ-aminovaleric acid ; Baclofen ; GABAB antagonist ; Spasticity

Springer Online Journal Archives 1860-2000

Medicine

Summary The action of δ-aminovaleric acid (AVA) on the muscle relaxant properties of baclofen, a GABAB receptor agonist, was investigated in two experimental models: (1) the pathologically increased muscle tone of the gastrocnemius muscle in spastic mutant Han-Wistar rats and (2) the Hoffmann (H)-reflex recorded from plantar foot muscles after electrical stimulation of the tibial nerve in barbiturate (60 mg/kg) anaesthetized rats. In both paradigms coadministration of AVA (500 nmol/5 μl) antagonized the muscle relaxant action of intrathecally applied baclofen (0.2–2 nmol), but failed to affect the muscle relaxant effects of intrathecally injected muscimol (2–20 nmol). In contrast, coadministration of bicuculline (1 nmol) did block the muscle relaxant action of muscimol, but failed to alter the effects of baclofen. When administered alone, bicuculline (1 nmol), or AVA (500 nmol–2 μmol) were without intrinsic action in both paradigms. In an additional series of experiments we investigated the action of AVA on a supraspinal effect of baclofen. Coadministration of AVA (12.5 nmol/0.5 μl) in the ventromedial thalamic nucleus antagonized the catalepsy induced by baclofen (ED50 10 pmol/0.5 μl), as indicated by an increase in ED50 of baclofen by a factor of 4.835 and a parallel shift of the probit-log dosage regression line to the right. The parallel shift seems to be consistent with a competitive mechanism of action of AVA. This study presents evidence that AVA antagonizes central pharmacological actions of baclofen at both spinal and supraspinal sites without affecting the actions of a GABAA agonist, muscimol.

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1432-1106

Catalepsy ; Electromyography ; GABA ; Limb rigidity ; Ventromedial thalamic nucleus

Springer Online Journal Archives 1860-2000

Medicine

Summary The cataleptic state induced by injection of the GABAmimetic drug muscimol into the rat's ventromedial thalamic nucleus (VM) was examined using an electromyographic (EMG) approach. Muscimol in doses up to 50 ng/0.5 μl injected into the VM induced a tonic EMG activity in the gastrocnemius muscle which is considered to be a measure of limb rigidity. This tonic EMG activity was found to be dose-dependent, GABA specific and locus specific. By recording EMG signals from chronically implanted electrodes in awake, unrestrained rats it was shown that muscular reactions serving to maintain the animal's static equilibrium were intact in the state of VM induced catalepsy. However, animals were unable to initiate movements or locomotion even when they were forced by strong external stimuli. It was found that the animals' immobility was due to an inability to induce a phasic activation of their muscles whereas tonic activation still occurred. It is concluded that (1) the rat's VM is part of a neuronal chain conducting information relevant for the expression of limb rigidity, (2) the VM is involved in the central mechanisms responsible for the phasic activation of a set of muscles.

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1432-1459

Infratentorial atrophy ; Idiopathic cerebellar ataxia ; Olivopontocerebellar atrophy ; Magnetic resonance imaging ; Computed tomography

Springer Online Journal Archives 1860-2000

Medicine

Summary The development of infratentorial atrophy in six patients suffering from idiopathic cerebellar ataxia of late onset was studied by a retrospective evaluation of consecutive computed tomography (CT) scans. Four patients had evidence of olivopontocerebellar atrophy (OPCA) both on clinical testing and magnetic resonance imaging (MRI). In these four patients, atrophy of the cerebellum and brain stem became visible at the same time and progressed in a roughly parallel manner, whereas in the remaining two the brain stem was left intact. In all patients with OPCA, definite brain-stem atrophy was visible earlier than the appearance of non-cerebellar clinical symptoms. The present data suggest that CT investigations at regular intervals may be of prognostic value in cerebellar ataxias.

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1432-1459

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1432-1459

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1432-1459

Idiopathic cerebellar ataxia ; Eye movements ; Magnetic resonance imaging

Springer Online Journal Archives 1860-2000

Medicine

Abstract Extensive oculomotor testing and quantitative MRI evaluation was performed in seven patients with idiopathic cerebellar ataxia without extracerebellar symptoms (IDCA-C) and in ten patients with additional extracerebellar symptoms (IDCA-P). The most severe oculomotor deficits were disturbed smooth pursuit, optokinetic nystagmus and suppression of the vestibulo-ocular reflex (VOR). The symptoms correlated well and consistently with the amount of atrophy of the flocculus and the dorsal vermis. These correlations, however, were not specific, and deficits also correlated with the amount of atrophy of other cerebellar structures. No correlation was found between saccade velocity and brain-stem atrophy or between saccade metrics and atrophy of the dorsal vermis. Although patients with IDCA-P had more severe oculomotor deficits than patients with IDCA-C, the pattern of the oculomotor disturbances was the same for both groups. Thus, eye movement analysis alone is not sufficient to distinguish between patients with pure cerebellar ataxia and those with additional extracerebellar symptoms.

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1432-1459

Key words Spinocerebellar ataxia ; Electrooculography ; Autosomal dominant cerebellar ataxia

Springer Online Journal Archives 1860-2000

Medicine

Abstract Forty-six patients suffering from autosomal dominant cerebellar ataxia type I (ADCA I) underwent to a genotype-phenotype correlation analysis by molecular genetic assignment to the spinocerebellar ataxia type 1, 2, or 3 (SCA1, SCA2, SCA3) genetic locus and electro-oculography. Oculomotor deficits that are attributed to dysfunction of cerebellar structures occurred in all three mutations without major differences between the groups. Gaze-evoked nystagmus, however, was not found to be associated with SCA2. Square wave jerks were exclusively observed in SCA3. The gain in vestibulo-ocular reflex was significantly impaired in SCA3 and SCA1. In SCA3 the severity of vestibular impairment increased with CAG repeat length. Severe saccade slowing was a highly characteristic feature of SCA2. In SCA3 saccade velocity was normal to mildly reduced while SCA1 fell into an intermediate range. The present data show that each mutation is associated with a distinct syndrome of oculomotor deficits. Reduced saccade velocity and the absence of both square-wave jerks and gaze-evoked nystagmus allow one SCA2 to be distinguished from SCA3 patients in almost all cases. The eye movement disorder of SCA1 patients, however, overlaps with both SCA2 and SCA3.

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1432-1459

Key words Cerebellar ataxia ; Autosomal dominance ; SCA2 locus

Springer Online Journal Archives 1860-2000

Medicine

Abstract 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), D12S1340(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.

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