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Biomedical subjects

E C Hirsch

Publications and source records attributed to E C Hirsch.

At least 73 records · Page 4Linked to original sources
PubMed1998

Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions.

Autosomal dominant cerebellar ataxia with progressive macular degeneration is caused by a CAG/glutamine repeat expansion in the SCA7 gene/protein. Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain. Nuclear inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7. They were also observed in other brain regions, including the cerebral cortex, not considered to be affected in the disease. Using confocal microscopy we showed that some inclusions were ubiquitinated, but to varying degrees, ranging from <1% in the cerebral cortex to 60% in the inferior olive. In addition, we also observed cytoplasmic staining using the 1C2 antibody, particularly in the supramarginal gyrus, the hippocampus, the thalamus, the lateral geniculate body and the pontine nuclei. These data confirm that the presence of intranuclear inclusions in neurons is a common characteristic of disorders caused by CAG/polyglutamine expansions, but unlike what has been reported for Huntington's disease, SCA1 and SCA3/MJD, in SCA7 the inclusions were not restricted to the sites of severe neuronal loss.

Ataxin-7↗
PubMed1998

Iron metabolism and Parkinson's disease.

There are at least three major reasons for thinking that iron participates in the mechanism of nerve cell death in Parkinson's disease (PD): (1) Iron catalyzes the formation of highly toxic hydroxyl radicals through the Fenton reaction. (2) Evidence suggests that oxidative stress participates in the mechanism of nerve cell death in PD. (3) Increased iron concentrations have been observed in the substantia nigra of patients with PD. In this review, we report data suggesting that the vulnerable neurons in PD are particularly sensitive to oxidative stress that may be induced by iron and then discuss the mechanisms by which iron levels may be increased in dopaminergic neurons in PD.

Cell Death↗
PubMed1997

Nuclear translocation of NF-kappaB in cholinergic neurons of patients with Alzheimer's disease.

NF-kappaB is a nuclear transcription factor involved in the control of numerous cellular functions, particularly regulation of survival. Translocation from the cytoplasm to the nucleus, an event essential for NK-kappaB activation, could be mediated through the low-affinity nerve growth factor receptor, p75, which has recently been shown to mediate cell death. In the human brain, p75 is exclusively expressed in cholinergic neurons of the basal forebrain. This population degenerates in Alzheimer's disease (AD). To investigate whether p75 could play a role in the vulnerability of these neurons via NF-kappaB activation, we studied the cellular distribution of NF-kappaB in the nucleus basalis of Meynert of four AD patients and four control subjects. The immunostaining observed both in AD patients and control subjects was limited to large, probably cholinergic, neurons. In AD, the proportion of neurons with nuclear NF-kappaB staining was significantly increased, suggesting an association between NF-kappaB functions and the process of cholinergic degeneration in AD.

Acetylcholine↗
PubMed1997

Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with parkinson disease.

Evidence from postmortem studies suggest an involvement of oxidative stress in the degeneration of dopaminergic neurons in Parkinson disease (PD) that have recently been shown to die by apoptosis, but the relationship between oxidative stress and apoptosis has not yet been elucidated. Activation of the transcription factor NF-kappaB is associated with oxidative stress-induced apoptosis in several nonneuronal in vitro models. To investigate whether it may play a role in PD, we looked for the translocation of NF-kappaB from the cytoplasm to the nucleus, evidence of its activation, in melanized neurons in the mesencephalon of postmortem human brain from five patients with idiopathic PD and seven matched control subjects. In PD patients, the proportion of dopaminergic neurons with immunoreactive NF-kappaB in their nuclei was more than 70-fold that in control subjects. A possible relationship between the nuclear localization of NF-kappaB in mesencephalic neurons of PD patients and oxidative stress in such neurons has been shown in vitro with primary cultures of rat mesencephalon, where translocation of NF-kappaB is preceded by a transient production of free radicals during apoptosis induced by activation of the sphingomyelin-dependent signaling pathway with C2-ceramide. The data suggest that this oxidant-mediated apoptogenic transduction pathway may play a role in the mechanism of neuronal death in PD.

Aged↗
PubMed1997

Choline acetyltransferase mRNA expression in the striatal neurons of patients with Alzheimer's disease.

Besides cortical pathology, Alzheimer's disease (AD) is associated with a massive loss of cholinergic neurons in the basal forebrain. The resulting cortical cholinergic depletion is thought to contribute to the major cognitive impairment described in Ad. A selective loss of cholinergic neurons has also been observed in the ventral striatum, despite the lack of any major neurochemical dysfunction in the striatum of patients with AD. To examined possible changes in the functional activity of the neurons that remain in the striatum of AD patients, the expression level of the gene coding for choline acetyltransferase (ChAT) was evaluated using in situ hybridization in the caudate nucleus, putamen and ventral striatum. Quantitative analysis showed (i) a marked decrease in the number of ChAT mRNA-positive neurons in the ventral striatum, and (ii) significantly reduced ChAT mRNA expression in the surviving cholinergic neurons of the ventral striatum, whereas it was only slightly decreased in those of the dorsal striatum. Our data support the hypothesis of a down-regulated expression of ChAT in striatal cholinergic neurons, especially in those most vulnerable to the neurodegenerative process. The subnormal ChAT mRNA content may be the consequence of changes in the level of transcription of the ChAT gene, possibly in relation to sustained suffering still present at the late stages of this disease. Furthermore, the involvement of the ventral striatum in Alzheimer's disease may account for some of the behavioral and motor dysfunctions often observed in patients with AD.

Aged↗
PubMed1997

The density of [125I]-transferrin binding sites on perikarya of melanized neurons of the substantia nigra is decreased in Parkinson's disease.

The density of [125I]-diferric-transferrin binding sites was investigated at the cellular level on melanized neurons located in the mesencephalon of patients with Parkinson's disease and control subjects, using quantitative autoradiography of in vitro incubated brain sections. In parkinsonian patients mean densities were reduced, the difference being statistically significant for the ventral tier of the substantia nigra, which is the subregion most affected by neuronal death in the disease. The absence of increase in the number of transferrin receptors on the perikarya within a population of neurons accumulating iron probably reflects the post-transcriptional gene regulation of the number of transferrin receptors that depends upon iron content in eukaryote cells.

Aged↗
PubMed1997

Expression of catalytic trkB gene in the striatum and the basal forebrain of patients with Alzheimer's disease: an in situ hybridization study.

The expression of catalytic trkB gene, encoding for the high affinity brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) receptor, was studied post mortem in the striatum and the nucleus basalis of Meynert of patients with Alzheimer's disease (AD) and control subjects, using in situ hybridization coupled with choline acetyltransferase immunohistochemistry. Microscopic examination of tissue sections showed labelling on perikarya of neurons but no labelling on glial cells. In the striatum, cholinergic as well as non-cholinergic and, presumably GABAergic, neurons expressed detectable levels of TrkB mRNA, while in the nucleus basalis of Meynert, only cholinergic neurons were labelled. Quantitative analysis of the in situ hybridization signal in cells of these two regions failed to demonstrate any significant difference between AD patients and control subjects. Normal levels of TrkB mRNA in the surviving cholinergic neurons of the nucleus basalis of Meynert suggest that these neurons could respond to an exogenous supply of BDNF and/or NT-4/5.

Aged↗
PubMed1997

Consequences of nigrostriatal denervation on the functioning of the basal ganglia in human and nonhuman primates: an in situ hybridization study of cytochrome oxidase subunit I mRNA.

To examine the consequences of nigrostriatal denervation and chronic levodopa (L-DOPA) treatment on functional activity of the basal ganglia, we analyzed, using in situ hybridization, the cellular expression of the mRNA encoding for cytochrome oxidase subunit I (COI mRNA), a molecular marker for functional neuronal activity, in the basal ganglia. This analysis was performed in monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Intoxication, some of which had been receiving L-DOPA, and in patients with Parkinson's disease (PD). In MPTP-intoxicated monkeys compared with control animals, COI mRNA expression was increased in the subthalamic nucleus (STN) and in the output nuclei of the basal ganglia, i.e., the internal segment of the globus pallidus and the substantia nigra pars reticulata. This increase was partially reversed by L-DOPA treatment. COI mRNA expression remained unchanged in the external segment of the globus pallidus (GPe). In PD patients, all of whom had been treated chronically by L-DOPA, COI mRNA expression in the analyzed basal ganglia structures was similar to that in control subjects. These results are in agreement with the accepted model of basal ganglia organization, to the extent that the output nuclei of the basal ganglia are considered to be overactive after nigrostriatal denervation, partly because of increased activity of excitatory afferents from the STN. Yet, our results would also seem to contradict this model, because the overactivity of the STN does not seem to be attributable to a hypoactivation of the GPe.

Aged↗
PubMed1997

Differential distribution of the normal and mutated forms of huntingtin in the human brain.

Huntington's disease is an inherited disorder caused by expansion of a CAG trinucleotide repeat in the IT15 gene, which leads to expansion of a polyglutamine tract within the protein called huntingtin. Despite the characterization of the IT15 gene and the mutation involved in the disease, the normal function of huntingtin and the effects of the mutation on its function and on its neuronal location remain unknown. To study whether mutated huntingtin has the same neuronal distribution and intracellular location as normal huntingtin, we analyzed immunohistochemically both forms of this protein in the brain of 5 controls and 5 patients with Huntington's disease. We show that the distribution of mutated huntingtin is, like that of the normal form, heterogeneous throughout the brain, but is not limited to vulnerable neurons in Huntington's disease, supporting the hypothesis that the presence of the mutated huntingtin in a neuron is not in itself sufficient to lead to neuronal death. Moreover, whereas normal huntingtin is detected in some neuronal perikarya, nerve fibers, and nerve endings, the mutated form is observed in some neuronal perikarya and proximal nerve processes but is not detectable in nerve endings. Our results suggest that the expression or processing of the mutated huntingtin in perikarya and nerve endings differs quantitatively or qualitatively from the expression of the normal form in the same neuronal compartments.

Adult↗
PubMed1997

Decreased TrkA gene expression in cholinergic neurons of the striatum and basal forebrain of patients with Alzheimer's disease.

In addition to cortical pathology, Alzheimer's disease is characterized by a loss of cholinergic neurons in the basal forebrain and the ventral striatum. Since cholinergic neurons which degenerate in Alzheimer's disease are sensitive to nerve growth factor, a link between nerve growth factor sensitivity and the vulnerability of cholinergic neurons has been suspected. The purpose of this study was to determine, in cholinergic neurons, the level of expression of TrkA, the high affinity receptor for nerve growth factor, in control subjects and Alzheimer patients. The study was performed by in situ hybridization using a 35S-labeled RNA probe complementary to human TrkA mRNA on immunohistochemically identified cholinergic neurons of the nucleus basalis of Meynert, the ventral striatum, and the putamen in postmortem brains of patients with clinically and neuropathologically confirmed Alzheimer's disease and control subjects. In patients with Alzheimer's disease, a decrease in TrkA mRNA expression was observed in the nucleus basalis of Meynert (-75%, P < 0.001) and the ventral striatum (-41%, P < 0.01), where the cholinergic neurons degenerate, and also in the anterior (-43%, P < 0.01) and posterior (-51%, P < 0.01) parts of the putamen, where they are spared but display precocious signs of cell alterations. These results, taken in conjunction with the reduced choline acetyltransferase activity and our previously published data showing a loss of high affinity nerve growth factor binding in both the dorsal and the ventral striatum of patients with Alzheimer's disease, indicate that receptor loss and the consequent decrease in trophic support may be associated with the degeneration of cholinergic neurons during Alzheimer's disease.

Aged↗
PubMed1997

Neuronal vulnerability in Parkinson's disease.

Although Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra not all dopaminergic neurons degenerate in this disease. This suggests that some specific factors make subpopulations of dopaminergic neurons more susceptible to the disease. Here, we show that the most vulnerable neurons are particularly sensitive to oxidative stress and rise in intracellular calcium concentrations. Because both events seem to occur in Parkinson's disease this may explain why some dopaminergic neurons degenerate and other do not.

Calcium↗
PubMed1997

Re-evaluation of the functional anatomy of the basal ganglia in normal and Parkinsonian states.

In the late 1980s, a functional and anatomical model of basal ganglia organization was proposed in order to explain the clinical syndrome of Parkinson's disease. According to this model, the pathological overactivity observed in the subthalamic nucleus and the output station of the basal ganglia plays a crucial role in the pathophysiology of the motor signs of Parkinson's disease. The hyperactivity of subthalamic neurons in Parkinsonism is viewed as a direct consequence of a pathological hypoactivity of the external segment of the pallidum. This article reviews recent data from different experimental approaches that challenge the established model of basal ganglia organization by reinterpreting the functional interaction between the external segment of the pallidum and the subthalamic nucleus in both the normal and pathological state. Indeed, recent neurobiochemical studies have rather unexpectedly shown that the GABAergic and metabolic activities of the external pallidum are not decreased in human and non-human primates with Parkinsonism. This absence of any decrease in activity might be explained by the functionally antagonistic influences of the striatal and subthalamic afferences within the external pallidum, as suggested by several anatomical studies. In addition, there are clues from electrophysiological studies to suggest that the hyperactivity found in the subthalamic neurons in Parkinsonism may not depend solely on the level of activity in the external pallidum. In such a framework, the hyperactivity of the subthalamic neurons would have to be explained, at least in part, by other sources of excitation or disinhibition. However, any explanation for the origin of the subthalamic overactivity in Parkinsonism remains speculative.

Animals↗
PubMed1997

Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive cell loss confined mostly to dopaminergic neurons of the substantia nigra. Several factors, including oxidative stress, and decreased activity of complex I mitochondrial respiratory chain, are involved in the degenerative process. Yet, the underlying mechanisms leading to dopaminergic cell loss remain elusive. Morphological assessment for different modes of cell death: apoptosis, necrosis or autophagic degeneration, can contribute significantly to the understanding of this neuronal loss. Ultrastructural examination revealed characteristics of apoptosis and autophagic degeneration in melanized neurons of the substantia nigra in PD patients. The results suggest that even at the final stage of the disease, the dopaminergic neurons are undergoing active process of cell death.

Aged↗
PubMed1997

Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging.

Morphological and biochemical alterations have been described in neurons of the aged human brain. However, the cell death process associated with neuronal senescence remains to be elucidated. Apoptosis and autophagic degeneration, two modes of programmed cell death described in embryogenesis and tissue renewal in adult, have been observed in nigral dopaminergic neurons in patients with Parkinson's disease. In the present study, we made the hypothesis that programmed cell death may be also involved in the death of nigral dopaminergic neurons occurring during aging. Cell death types were defined by morphological criteria identified at subcellular level. We thus performed an ultrastructural analysis in order to search for apoptotic and autophagic features in melanized neurons of the substantia nigra in four normal aged subjects. Morphological characteristics of apoptosis, such as contact loss with surrounding tissues, cell shrinkage and chromatin condensation, were found in 2% of the total number of melanized neurons analyzed. Although endoplasmic reticulum appeared normal, mitochrondria were markedly shrunken. Fragments of melanized neurons were found in glial cells. Autophagic degeneration or necrosis were not detected in melanized neurons. Signs of oxidative stress, such as vacuolation of mitochondria, were observed in melanized neurons devoid of apoptotic features. These findings demonstrate that apoptosis is involved in cell death of nigral dopaminergic neurons during normal aging. Since morphological abnormalities found in this study, such as marked mitochondrial shrinkage in apoptotic neurons, were not observed in patients with Parkinson's disease, the mechanisms underlying apoptosis may be different in aging and pathology.

Aged↗
PubMed1996

Regional and cellular presenilin 2 (STM2) gene expression in the human brain.

Presenilin 2 (STM2) is a recently cloned gene involved in some forms of early onset Alzheimer's disease with autosomal dominant inheritance. Here we report the regional and cellular distribution of STM2 mRNA in the normal human central nervous system. Using in situ hybridization. STM2 gene expression was shown to be confined exclusively to neurones in the central nervous system. A high level of STM2 mRNA expression was observed in the cerebral cortex and the hippocampus, more particularly on pyramidal neurones of Ammon's horn and granular neurones of the dentate gyrus. STM2 mRNA was also detected in Purkinje cells and granular cells of the cerebellum, and in neurones of the striatum and the nucleus basalis of Meynert. Taken together, these results suggest that the expression of STM2 mRNA is not restricted to the neuronal populations that are known to degenerate in Alzheimer's disease.

Aged↗
PubMed1996

Expression of glutamate receptors in the human and rat basal ganglia: effect of the dopaminergic denervation on AMPA receptor gene expression in the striatopallidal complex in Parkinson's disease and rat with 6-OHDA lesion.

The overactivity of subthalamopallidal and corticostriatal glutamatergic neurons observed in Parkinson's disease (PD) suggests that antagonists of glutamate receptor could be used to alleviate the motor symptoms of the disease. In this study, we analysed two features of the striatopallidal complex: (1) the distribution of alpha-amino-3 hydroxy-5-methyl-4-isoxasol-propionate (AMPA) and kainate receptors and their corresponding mRNA by immunohistochemistry and in situ hybridisation and (2) the effect of dopaminergic denervation on AMPA receptor gene expression in PD patients and rats with 6-hydroxydopamine (6-OHDA)-induced degeneration of the nigrostriatal dopaminergic system. All AMPA receptor mRNAs and proteins (GluR1-4) were detected in the internal segment of the globus pallidus (GPi). Among kainate receptors, only KA1 and KA2 were detectable and only at a low level. Only GluR4 protein was detected in the neuropil of the GPi. In the striatum, GluR1, GluR2, and GluR3 were detected in about 70% of medium-sized and large neurons. By contrast, GluR4 mRNA was detected in only a small number of large and medium-sized neurons. Among kainate receptors, GluR6, GluR7, and KA2 were detected in about 50-60% of medium-sized neurons, whereas GluR5 and KA1 were restricted to 1-2% and 20-30% of these neurons, respectively. These results suggest that antagonists of AMPA and kainate receptors could be effective in alleviating motor symptoms in Parkinson's disease by blocking the overstimulation of pallidal and striatal neurons by glutamate. A significant decrease in GluR1 gene expression (-33%) was observed in the neurons of the GPi in PD patients and in rat entopeduncular nucleus ipsilateral to the 6-OHDA lesion (-20%). GluR2, GluR3, and GluR4 mRNA levels in the GPi and GluR1-4 levels in the striatum were unchanged in PD patients and 6-OHDA-lesioned rats compared with their respective controls. These data suggest that dopamine positively regulates only GluR1 gene expression in the GPi.

Animals↗