U. Wüllner | Bonn Universität (original) (raw)
Papers by U. Wüllner
Basal Ganglia, 2012
ABSTRACT To delineate possibly distinct cognitive impairment in patients with multiple system atr... more ABSTRACT To delineate possibly distinct cognitive impairment in patients with multiple system atrophy (MSA) of cerebellar (MSA-C) and striatonigral (MSA-P) predominance, we employed two experimental tasks sensitive to striatal lesions: the Weather-Prediction Task (WPT) and the Object Alternation Task (OAT). Only MSA-P (n = 10) patients showed reduced learning in the WPT and were impaired at maintaining the alternation rule in the OAT, compared to MSA-C (n = 10) and matched controls (n = 26). Both MSA-groups were impaired regarding digit span and verbal fluency.This distinct pattern of cognitive impairment reflects the prevailing involvement of striato-thalamo-cortical circuits in MSA-P patients and of cerebellar-prefrontal circuits in MSA-C patients. The specific cognitive impairments correspond to the type of motor predominance in MSA.
Journal of Neural Transmission. Supplementa, 1997
Apoptotic neuronal death is a key mechanism that regulates the elimination of neuronal precursor ... more 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.
Klinische Neurophysiologie, 2006
The Cerebellum, 2013
Whole body vibration (WBV) is a biomechanical treatment used widely in professional sports and re... more Whole body vibration (WBV) is a biomechanical treatment used widely in professional sports and rehabilitation. We examined the effect of stochastic WBV on ataxia in spinocerebellar ataxia types 1, 2, 3, and 6 (SCA 1, 2, 3 and 6) in a single-center double-blind sham-controlled study. Stochastic WBV was applied on four sequent days, each treatment consisting of five stimulus trains of 60-s duration at a frequency of 6.5 Hz and 60-s resting time between stimuli (n = 17). Patients allocated to the sham group received the same treatment with 1 Hz (n = 15). All patients were rated at baseline and after the last treatment using clinical scores (SARA, SCAFI, and INAS). After treatment, we found significant improvements of gait, posture, and speed of speech in the verum group while limb kinetics and ataxia of speech did not respond. Stochastic WBV might act on proprioceptive mechanisms and could also stimulate non-cerebellar/compensatory mechanisms. But at present, the involved cellular mechanism and the presumed neuronal loops cannot be deciphered. Thus, future work is needed to understand the mechanisms of whole body vibration. Finally, the use of stochastic WBV could provide a supplementation to treat ataxia in SCA and can be combined with physiotherapeutical motor training.
Parkinsonism & Related Disorders, 2010
A common subset of genetic risk factors for Parkinson's disease (PD) and essential tremor... more A common subset of genetic risk factors for Parkinson's disease (PD) and essential tremor (ET) has been postulated. Recently, an association between the dopamine D(3) receptor (DRD3) Ser9Gly polymorphism and ET has been reported. We studied whether PD tremor is influenced by Ser9Gly in a genetic association study based on the gene bank of the German Competence Network on Parkinson's disease. The study included analyses of motor predominance (mixed, hypokinetic, and tremor), and tremor type (resting, postural, and action). We did not identify any effect of DRD3 Ser9Gly on tremor in PD, even when regarding various symptom combinations to avoid missing a weak effect on the phenotype. Additional studies incorporating symptoms at disease onset, and grading of tremor response to dopaminergic therapy, are warranted.
Neurology, 2001
Figure. 18 F-fluorodeoxyglucose (FDG) PET during a relapse after withdrawal of methotrexate. FDG ... more Figure. 18 F-fluorodeoxyglucose (FDG) PET during a relapse after withdrawal of methotrexate. FDG uptake is enhanced in the right caput nuclei caudati (CNC) as compared with the contralateral side. Regions of interest in this plane revealed maximal standard uptake values of 6.3 (right CNC) and 5.8 (left CNC).
Movement Disorders, 2000
Autosomal-dominant cerebellar ataxias (ADCA) may present as progressive or paroxysmal disorders. ... more Autosomal-dominant cerebellar ataxias (ADCA) may present as progressive or paroxysmal disorders. While the progressive ataxias have been named spinocerebellar ataxias (SCA), the paroxysmal disorders are designated episodic ataxias (EA). Until now, three different mutational mechanisms resulting in distinctive pathogenesis have been identified. The first type of mutation present in SCA1, SCA2, SCA3, and SCA7 is an expanded CAG repeat in genes of unknown function that are translated into proteins with expanded polyglutamine tracts. A common ultrastructural feature of these disorders is the formation of neuronal intranuclear inclusions (NII) harboring the expanded disease proteins and a variety of other proteins. The pathogenic role of these inclusions has yet to be clarified. A second group of disorders is the result of mutations in genes that code for ion channels. In EA-1, a disorder characterized by episodes of ataxia provoked by movement and startle, missense mutations in a potassium channel gene, KCNA1, have been found. Patients with EA-2, another form of paroxysmal ataxia, carry nonsense mutations of the gene encoding the ␣ 1A voltage-dependent calcium channel subunit, CACNA1A, that are predicted to result in truncated channel proteins. In SCA6, a progressive ataxia, an expanded CAG repeat in the 3Ј translated region of the CACNA1A gene, has been found. The third type of mutation is an untranslated CTG expansion resembling the mutation found in myotonic dystrophy. It is associated with a progressive ataxia, SCA8.
Journal of the Neurological Sciences, 2013
p = 0.012). Significant improvements in UPDRS-motor scores were also observed (p = 0.007). There ... more p = 0.012). Significant improvements in UPDRS-motor scores were also observed (p = 0.007). There were no significant differences between groups for ADL or CGI scores. Rasagiline was well-tolerated, with no significant difference in percentage of patients with AEs (64.2% vs. 61.0%) or serious AEs (4.9% vs. 3.0%) versus placebo. Only 11 patients required rescue levodopa during the study. Conclusions: Addition of rasagiline significantly improved motor symptoms in patients sub-optimally controlled with DA monotherapy, and was well-tolerated.
Journal of Neurology, Neurosurgery & Psychiatry, 2008
Journal of Neurology, 2009
Journal of Neurochemistry, 2002
Neuronally differentiated P012 cells undergo synchronous apoptosis when deprived of nerve growth ... more Neuronally differentiated P012 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-a-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-i blocked NGF withdrawal-induced apoptosis, activation of caspases, and ROS generation, showing that they function upstream of caspases. Coexpression of BCL-2 and BAG-i was more protective than expression of either protein alone.
Journal of Neural Transmission, 2007
We identified 221 patients with probable multiple system atrophy (MSA) among 4770 patients enroll... more We identified 221 patients with probable multiple system atrophy (MSA) among 4770 patients enrolled in the multicentre registry of the German Competence Network on Parkinson's disease (PD) according to the established consensus criteria to characterize their clinical presentation. Analyses of more than 100 recorded clinical items revealed several specifics: I) 50% of patients with probable MSA had asymmetry of symptoms at disease onset and tremor at rest was present in 25%; II) a positive response to levodopa was recorded in 51% of patients identified initially with severe autonomic failure and cerebellar ataxia; III) a positive family history was recorded in 11% (n ¼ 23), two of these patients were identified with spinocerebellar ataxia type 3 (SCA3). Thus asymmetry of symptoms, tremor at rest and a positive response to levodopa are not as specific for idiopathic PD as believed previously. Patients with SCA3 may present with the clinical features of MSA.
Journal of Neural Transmission, 1995
Aging, disease and nerve cell death Apoptosis, or programmed cell death, is characterized by an a... more Aging, disease and nerve cell death Apoptosis, or programmed cell death, is characterized by an active auto-destruction of ceils. Several proteins inducing (CED-3) or preventing (CED-9) neuronal death have been described in the nematode C. elegans. There is an homology between these proteins and BCL-2 and ICE (Interleukine-l~-Converting (Enzyme) in vertebrates. The cascade of biochemical events leading to this active neuronal "suicide" is triggered by initiating factors such as genotoxicity, growth factors deprivation, cytokines (TNFc0.
Human Molecular Genetics, 2009
The nuclear presence of the expanded disease proteins is of critical importance for the pathogene... more The nuclear presence of the expanded disease proteins is of critical importance for the pathogeneses of polyglutamine diseases. Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). Serine 340 and 352 within the third ubiquitin-interacting motif of ATXN3 were particularly important for nuclear localization of normal and expanded ATXN3 and mutation of these sites robustly reduced the formation of nuclear inclusions; a putative nuclear leader sequence was not required. ATXN3 associated with CK2a and pharmacological inhibition of CK2 decreased nuclear ATXN3 levels and the formation of nuclear inclusions. Moreover, we found that ATXN3 shifted to the nucleus upon thermal stress in a CK2-dependent manner, indicating a key role of CK2-mediated phosphorylation of ATXN3 in SCA3 pathophysiology.
Experimental Brain Research, 1988
The action of d-aminovaleric acid (AVA) on the muscle relaxant properties of baclofen, a GABAB re... more The action of d-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
Cell Death & Differentiation, 1998
In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resembl... more In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.
Archives of Neurology, 1993
OBJECTIVE--To clarify the nosological classification of late-onset Friedreich's ataxia (LOFA)... more OBJECTIVE--To clarify the nosological classification of late-onset Friedreich's ataxia (LOFA), ie, patients who have later onset of Friedreich's ataxia (FRDA), often after 25 years of age. DESIGN--Comparison of clinical examination data, nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging of a family with LOFA with a group of patients with FRDA. Genetic linkage analysis was performed in the family with LOFA. SETTING--Referral center. PATIENTS--Thirteen patients satisfied classic diagnostic criteria of FRDA, and three patients from one family satisfied all diagnostic criteria of FRDA but with disease onset after 25 years. RESULTS--Results of nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging in patients with LOFA closely corresponded to observations made in patients with FRDA. In addition, genetic linkage analysis using markers tightly linked to the FRDA locus on chromosome 9 showed that all affected members of the LOFA family, but not their unaffected siblings, had inherited identical paternal and maternal genotypes. CONCLUSIONS--Data suggest that LOFA may also result from mutation within the FRDA locus.
Annals of Neurology, 2005
Aktuelle Neurologie, 2006
Basal Ganglia, 2012
ABSTRACT To delineate possibly distinct cognitive impairment in patients with multiple system atr... more ABSTRACT To delineate possibly distinct cognitive impairment in patients with multiple system atrophy (MSA) of cerebellar (MSA-C) and striatonigral (MSA-P) predominance, we employed two experimental tasks sensitive to striatal lesions: the Weather-Prediction Task (WPT) and the Object Alternation Task (OAT). Only MSA-P (n = 10) patients showed reduced learning in the WPT and were impaired at maintaining the alternation rule in the OAT, compared to MSA-C (n = 10) and matched controls (n = 26). Both MSA-groups were impaired regarding digit span and verbal fluency.This distinct pattern of cognitive impairment reflects the prevailing involvement of striato-thalamo-cortical circuits in MSA-P patients and of cerebellar-prefrontal circuits in MSA-C patients. The specific cognitive impairments correspond to the type of motor predominance in MSA.
Journal of Neural Transmission. Supplementa, 1997
Apoptotic neuronal death is a key mechanism that regulates the elimination of neuronal precursor ... more 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.
Klinische Neurophysiologie, 2006
The Cerebellum, 2013
Whole body vibration (WBV) is a biomechanical treatment used widely in professional sports and re... more Whole body vibration (WBV) is a biomechanical treatment used widely in professional sports and rehabilitation. We examined the effect of stochastic WBV on ataxia in spinocerebellar ataxia types 1, 2, 3, and 6 (SCA 1, 2, 3 and 6) in a single-center double-blind sham-controlled study. Stochastic WBV was applied on four sequent days, each treatment consisting of five stimulus trains of 60-s duration at a frequency of 6.5 Hz and 60-s resting time between stimuli (n = 17). Patients allocated to the sham group received the same treatment with 1 Hz (n = 15). All patients were rated at baseline and after the last treatment using clinical scores (SARA, SCAFI, and INAS). After treatment, we found significant improvements of gait, posture, and speed of speech in the verum group while limb kinetics and ataxia of speech did not respond. Stochastic WBV might act on proprioceptive mechanisms and could also stimulate non-cerebellar/compensatory mechanisms. But at present, the involved cellular mechanism and the presumed neuronal loops cannot be deciphered. Thus, future work is needed to understand the mechanisms of whole body vibration. Finally, the use of stochastic WBV could provide a supplementation to treat ataxia in SCA and can be combined with physiotherapeutical motor training.
Parkinsonism & Related Disorders, 2010
A common subset of genetic risk factors for Parkinson's disease (PD) and essential tremor... more A common subset of genetic risk factors for Parkinson's disease (PD) and essential tremor (ET) has been postulated. Recently, an association between the dopamine D(3) receptor (DRD3) Ser9Gly polymorphism and ET has been reported. We studied whether PD tremor is influenced by Ser9Gly in a genetic association study based on the gene bank of the German Competence Network on Parkinson's disease. The study included analyses of motor predominance (mixed, hypokinetic, and tremor), and tremor type (resting, postural, and action). We did not identify any effect of DRD3 Ser9Gly on tremor in PD, even when regarding various symptom combinations to avoid missing a weak effect on the phenotype. Additional studies incorporating symptoms at disease onset, and grading of tremor response to dopaminergic therapy, are warranted.
Neurology, 2001
Figure. 18 F-fluorodeoxyglucose (FDG) PET during a relapse after withdrawal of methotrexate. FDG ... more Figure. 18 F-fluorodeoxyglucose (FDG) PET during a relapse after withdrawal of methotrexate. FDG uptake is enhanced in the right caput nuclei caudati (CNC) as compared with the contralateral side. Regions of interest in this plane revealed maximal standard uptake values of 6.3 (right CNC) and 5.8 (left CNC).
Movement Disorders, 2000
Autosomal-dominant cerebellar ataxias (ADCA) may present as progressive or paroxysmal disorders. ... more Autosomal-dominant cerebellar ataxias (ADCA) may present as progressive or paroxysmal disorders. While the progressive ataxias have been named spinocerebellar ataxias (SCA), the paroxysmal disorders are designated episodic ataxias (EA). Until now, three different mutational mechanisms resulting in distinctive pathogenesis have been identified. The first type of mutation present in SCA1, SCA2, SCA3, and SCA7 is an expanded CAG repeat in genes of unknown function that are translated into proteins with expanded polyglutamine tracts. A common ultrastructural feature of these disorders is the formation of neuronal intranuclear inclusions (NII) harboring the expanded disease proteins and a variety of other proteins. The pathogenic role of these inclusions has yet to be clarified. A second group of disorders is the result of mutations in genes that code for ion channels. In EA-1, a disorder characterized by episodes of ataxia provoked by movement and startle, missense mutations in a potassium channel gene, KCNA1, have been found. Patients with EA-2, another form of paroxysmal ataxia, carry nonsense mutations of the gene encoding the ␣ 1A voltage-dependent calcium channel subunit, CACNA1A, that are predicted to result in truncated channel proteins. In SCA6, a progressive ataxia, an expanded CAG repeat in the 3Ј translated region of the CACNA1A gene, has been found. The third type of mutation is an untranslated CTG expansion resembling the mutation found in myotonic dystrophy. It is associated with a progressive ataxia, SCA8.
Journal of the Neurological Sciences, 2013
p = 0.012). Significant improvements in UPDRS-motor scores were also observed (p = 0.007). There ... more p = 0.012). Significant improvements in UPDRS-motor scores were also observed (p = 0.007). There were no significant differences between groups for ADL or CGI scores. Rasagiline was well-tolerated, with no significant difference in percentage of patients with AEs (64.2% vs. 61.0%) or serious AEs (4.9% vs. 3.0%) versus placebo. Only 11 patients required rescue levodopa during the study. Conclusions: Addition of rasagiline significantly improved motor symptoms in patients sub-optimally controlled with DA monotherapy, and was well-tolerated.
Journal of Neurology, Neurosurgery & Psychiatry, 2008
Journal of Neurology, 2009
Journal of Neurochemistry, 2002
Neuronally differentiated P012 cells undergo synchronous apoptosis when deprived of nerve growth ... more Neuronally differentiated P012 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-a-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-i blocked NGF withdrawal-induced apoptosis, activation of caspases, and ROS generation, showing that they function upstream of caspases. Coexpression of BCL-2 and BAG-i was more protective than expression of either protein alone.
Journal of Neural Transmission, 2007
We identified 221 patients with probable multiple system atrophy (MSA) among 4770 patients enroll... more We identified 221 patients with probable multiple system atrophy (MSA) among 4770 patients enrolled in the multicentre registry of the German Competence Network on Parkinson's disease (PD) according to the established consensus criteria to characterize their clinical presentation. Analyses of more than 100 recorded clinical items revealed several specifics: I) 50% of patients with probable MSA had asymmetry of symptoms at disease onset and tremor at rest was present in 25%; II) a positive response to levodopa was recorded in 51% of patients identified initially with severe autonomic failure and cerebellar ataxia; III) a positive family history was recorded in 11% (n ¼ 23), two of these patients were identified with spinocerebellar ataxia type 3 (SCA3). Thus asymmetry of symptoms, tremor at rest and a positive response to levodopa are not as specific for idiopathic PD as believed previously. Patients with SCA3 may present with the clinical features of MSA.
Journal of Neural Transmission, 1995
Aging, disease and nerve cell death Apoptosis, or programmed cell death, is characterized by an a... more Aging, disease and nerve cell death Apoptosis, or programmed cell death, is characterized by an active auto-destruction of ceils. Several proteins inducing (CED-3) or preventing (CED-9) neuronal death have been described in the nematode C. elegans. There is an homology between these proteins and BCL-2 and ICE (Interleukine-l~-Converting (Enzyme) in vertebrates. The cascade of biochemical events leading to this active neuronal "suicide" is triggered by initiating factors such as genotoxicity, growth factors deprivation, cytokines (TNFc0.
Human Molecular Genetics, 2009
The nuclear presence of the expanded disease proteins is of critical importance for the pathogene... more The nuclear presence of the expanded disease proteins is of critical importance for the pathogeneses of polyglutamine diseases. Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). Serine 340 and 352 within the third ubiquitin-interacting motif of ATXN3 were particularly important for nuclear localization of normal and expanded ATXN3 and mutation of these sites robustly reduced the formation of nuclear inclusions; a putative nuclear leader sequence was not required. ATXN3 associated with CK2a and pharmacological inhibition of CK2 decreased nuclear ATXN3 levels and the formation of nuclear inclusions. Moreover, we found that ATXN3 shifted to the nucleus upon thermal stress in a CK2-dependent manner, indicating a key role of CK2-mediated phosphorylation of ATXN3 in SCA3 pathophysiology.
Experimental Brain Research, 1988
The action of d-aminovaleric acid (AVA) on the muscle relaxant properties of baclofen, a GABAB re... more The action of d-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
Cell Death & Differentiation, 1998
In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resembl... more In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.
Archives of Neurology, 1993
OBJECTIVE--To clarify the nosological classification of late-onset Friedreich's ataxia (LOFA)... more OBJECTIVE--To clarify the nosological classification of late-onset Friedreich's ataxia (LOFA), ie, patients who have later onset of Friedreich's ataxia (FRDA), often after 25 years of age. DESIGN--Comparison of clinical examination data, nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging of a family with LOFA with a group of patients with FRDA. Genetic linkage analysis was performed in the family with LOFA. SETTING--Referral center. PATIENTS--Thirteen patients satisfied classic diagnostic criteria of FRDA, and three patients from one family satisfied all diagnostic criteria of FRDA but with disease onset after 25 years. RESULTS--Results of nerve conduction studies, electronystagmographic recording, and magnetic resonance imaging in patients with LOFA closely corresponded to observations made in patients with FRDA. In addition, genetic linkage analysis using markers tightly linked to the FRDA locus on chromosome 9 showed that all affected members of the LOFA family, but not their unaffected siblings, had inherited identical paternal and maternal genotypes. CONCLUSIONS--Data suggest that LOFA may also result from mutation within the FRDA locus.
Annals of Neurology, 2005
Aktuelle Neurologie, 2006