Dopamine denervation, age of onset, and Parkinson's disease.
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Age of Onset↗
Biomedical subjects
F Javoy-Agid
Publications and source records attributed to F Javoy-Agid.
Loss of striatal high affinity NGF binding sites in progressive supranuclear palsy but not in Parkinson's disease.
125I-Nerve growth factor (NGF) binding sites were analyzed by autoradiography in the striatum of 3 control subjects, 3 patients with Parkinson's disease and 3 patients with progressive supranuclear palsy. A high level of 125I-NGF binding was observed (0.3-0.4 fmol/mg of tissue equivalent) in the striatum and the nucleus basalis of Meynert of control patients. Pockets of lower 125I-NGF binding corresponding to acetylcholinesterase-poor striosomes were detected in the striatum of control subjects and patients with Parkinson's disease or progressive supranuclear palsy. When compared to controls, the density of 125I-NGF binding sites was reduced by 30% in the striatum of patients with progressive supranuclear palsy but not reduced in that of patients with Parkinson's disease. 125I-NGF binding was not significantly decreased in the nucleus basalis of Meynert in either diseases. Since NGF receptors are thought to be localized on cholinergic neurons in the striatum, the decrease in NGF binding is compatible with the loss of cholinergic neurons reported in the striatum from PSP patients.
Aged↗
Monoamine vesicular uptake sites in patients with Parkinson's disease and Alzheimer's disease, as measured by tritiated dihydrotetrabenazine autoradiography.
The monoaminergic innervation of the caudate nucleus, putamen and ventral striatum was investigated post mortem, in patients with Parkinson's and Alzheimer's disease as compared to control subjects, by autoradiographic detection of tritiated dihydrotetrabenazine (3H-TBZOH), a specific high affinity ligand of the vesicular monoamine transporter. The binding of 3H-TBZOH was specific and saturable (Kd 5.3 nM). In control striatum, the pattern of distribution of 3H-TBZOH binding was heterogeneous, with higher binding levels in the 'matrix' than in the 'striosome' compartment. Changes in ligand binding levels were observed in the pathological brains compared to controls. In Parkinson's disease (PD), characterized by a severe damage of mesostriatal dopaminergic neurons, the density of 3H-TBZOH binding was reduced. A severe decrease in 3H-TBZOH binding was observed in all parts of the striatum (caudate nucleus: -80%, putamen: -86%, ventral striatum: -94%) in PD brains. The data corroborate the deficiency in striatal dopaminergic transmission and suggest that in PD brains dopaminergic terminals have disappeared and/or no longer contain synaptic vesicles. In Alzheimer's disease (AD), 3H-TBZOH binding was significantly reduced by 57% in the ventral striatum and not in the caudate nucleus and putamen. The specific decrease of monoaminergic transporter levels in the ventral striatum confirm that this nucleus is a target area in AD.
Aged↗
Galanin receptors in human hypothalamus: biochemical and structural analysis.
Galanin receptors have been characterized in normal human hypothalamus using 125I-galanin binding assays. Competition experiments of porcine 125I-galanin binding to human hypothalamic membranes with native human, porcine and rat galanin (10(-11) M to 10(-8) M) gave comparable results with IC50 close to 0.1 nM. Scatchard analysis indicated one type of high affinity binding sites (Kd = 0.11 nM) with a capacity of 460 fmol/mg protein. Galanin-(1-15) and galanin-(2-29) inhibited tracer binding (IC50 = 1.5 nM), galanin-(3-29) and galanin-(10-29) being inactive. The galanin receptor antagonist, galantide, 10(-14) M to 10(-8) M, also strongly displaced binding of 125I-galanin to the human receptor (IC50 close to 0.15 nM). Guanine nucleotides (from 10(-8) M to 10(-4) M) decreased tracer binding to human membranes by increasing the dissociation of the galanin-receptor complexes. Structural analysis by covalent labelling indicated that the human galanin receptor behaves as a monomeric protein with a molecular mass of 54,000 daltons.
Aged↗
Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease.
Activated glial cells observed in the substantia nigra in Parkinson's disease may participate in the mechanism of nerve cell death by providing toxic substances such as cytokines. Among these compounds, tumor necrosis factor-alpha (TNF) is of interest because it can provoke cell death. We detected TNF-immunoreactive glial cells in the substantia nigra of parkinsonian patients but not in those of control subjects. Immunoreactivity for TNF receptors was found in cell bodies and processes of most dopaminergic neurons of control and parkinsonian subjects, suggesting that nigral dopaminergic neurons might be sensitive to TNF produced in Parkinson's disease. These results suggest that TNF may participate in the degenerative processes occurring in Parkinson's disease, at least after a primary insult inducing a reactive gliosis.
Aged↗
Sulfonylurea binding sites in normal human brain and in Parkinson's disease, progressive supranuclear palsy and Huntington's disease.
In human brain, [3H]glibenclamide binds with high affinity (KD about 3.5 nM) to sulfonylurea binding sites which are associated with ATP-sensitive potassium (KATP) channels. Regarding to the important neuromodulatory action of KATP channels in some neuronal populations, sulfonylurea binding sites were measured in several cortical areas (frontal and temporal cortex, hippocampus) and striatum (caudate nucleus and putamen) in controls and patients with Parkinson's disease or progressive supranuclear palsy. There was no modification of [3H]glibenclamide specific binding in the cerebral regions studied in both pathologies. These results indicate that KATP channels do not seem to be involved in the pathophysiology of these degenerative processes. Brain samples from five patients with Huntington's disease were studied. A small decrease in sulfonylurea binding sites was measured in the frontal cortex, caudate nucleus and putamen which could be due to the loss of either neurons or nerve endings. This low decrease contrasts with the dramatic diminution of many other markers associated with the profound striatal degeneration occurring in Huntington's disease.
ATP-Binding Cassette Transporters↗
Dopamine transporter messenger RNA in Parkinson's disease and control substantia nigra neurons.
Dopamine transporter messenger RNA (mRNA) expression was assessed by in situ hybridization over individual pigmented neurons from the substantia nigra pars compacta in midbrain sections from 7 parkinsonian and 7 age-matched, neurologically normal patients. In the normal control brains, high levels of expression of dopamine transporter mRNA were noted over pigmented neurons in the substantia nigra pars compacta; neurons in the adjacent nucleus paranigralis of the ventral tegmental area displayed less hybridization. Nigra compacta neurons surviving in brains of patients with Parkinson's disease displayed only 57% of the dopamine transporter mRNA hybridization intensity displayed by nigral neurons in normal control brains. The disease-related decrease in the apparent level of dopamine transporter mRNA expression in remaining neurons could reflect neuronal dysfunction. Conceivably, it might also reflect differential vulnerability of those neurons that initially expressed higher levels of this transporter to the insult of parkinsonism.
Aged↗
Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopa and GM1 ganglioside therapy.
Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein found in the remaining cells. The reduced expression of tyrosine hydroxylase may be due to either the evolving neurodegenerative process or its downregulation, possibly secondary to chronic levodopa treatment. The cellular content of tyrosine hydroxylase was determined in the mesencephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonian by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatment) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalon of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, the cellular content of tyrosine hydroxylase was reduced by 40% in the surviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosine hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expression of tyrosine hydroxylase found in nigral dopaminergic neurons after partial degeneration of the mesostriatal dopaminergic system is not influenced by levodopa treatment and is partially reversed by GM1 ganglioside administration.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia.
Reduced glutathione (GSH) and oxidized glutathione (GSSG) levels were measured in various brain areas (substantia nigra, putamen, caudate nucleus, globus pallidus, and cerebral cortex) from patients dying with Parkinson's disease, progressive supranuclear palsy, multiple-system atrophy, and Huntington's disease and from control subjects with no neuropathological changes in substantia nigra. GSH levels were reduced in substantia nigra in Parkinson's disease patients (40% compared to control subjects) and GSSG levels were marginally (29%) but insignificantly elevated; there were no changes in other brain areas. The only significant change in multiple-system atrophy was an increase of GSH (196%) coupled with a reduction of GSSG (60%) in the globus pallidus. The only change in progressive supranuclear palsy was a reduced level of GSH in the caudate nucleus (51%). The only change in Huntington's disease was a reduction of GSSG in the caudate nucleus (50%). Despite profound nigral cell loss in the substantia nigra in Parkinson's disease, multiple-system atrophy, and progressive supranuclear palsy, the level of GSH in the substantia nigra was significantly reduced only in Parkinson's disease. This suggests that the change in GSH in Parkinson's disease is not solely due to nigral cell death, or entirely explained by drug therapy, for multiple-system atrophy patients were also treated with levodopa. The altered GSH/GSSG ratio in the substantia nigra in Parkinson's disease is consistent with the concept of oxidative stress as a major component in the pathogenesis of nigral cell death in Parkinson's disease.
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Identification of new human myelin basic protein transcripts in the immune and central nervous systems.
Five new myelin basic protein (MBP) transcripts were identified which each have preferential sites of expression in adult human brain and immune system. They contain a novel 5' coding region which presents extensive sequence similarity to the mouse 0' region. One of these ribonucleic acid (RNA) species, HMBPR1, is found essentially, if not only, in haemopoietic and immune cells. Two alternatively spliced transcripts called MBP2a and c are only expressed in the central nervous system (CNS). In addition, the two other transcripts are expressed in both immune and nervous systems. Thus, the MBP locus can generate multiple forms of RNA, whose start sites and splicing depend on the tissue in which they are expressed. The presence of an MBP transcript specifically expressed in the adult human immune system suggests previously unsuspected functions related to the pathogenesis of multiple sclerosis.
Amino Acid Sequence↗
Cholinergic and peptidergic systems in PSP.
PSP is associated with a widespread cholinergic deficit likely corresponding to a loss in cholinergic neurons. The cholinergic damage dramatically affects the basal ganglia and specific cell groups of the mesencephalon and pons. This provides an anatomically defined basis for motor and supranuclear oculomotor syndromes characteristic of PSP. Unlike Alzheimer's disease and Parkinson's disease with dementia, the disease is not associated with a marked cholinergic deficiency in the cerebral cortex. Various peptides are present at normal concentrations in extrapyramidal and limbic subcortical areas in brains of patients with PSP. Of particular interest, is somatostatin, the levels of which are subnormal in cerebral cortex of patients with dementia of Alzheimer' or Parkinson's disease type.
Acetylcholine↗
Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon.
Dopaminergic (DA) cells of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) display differences in their topography, biochemistry and susceptibility to pathological processes. Neuronal dopamine concentration is regulated in large part by tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, and by the dopamine reuptake system. In the present study, TH protein, TH mRNA and dopamine membrane transporter (DAT) mRNA were quantified at cellular level in 4 arbitrary subregions of the rat ventral mesencephalon (lateral, middle, medial SNC and VTA), using in situ hybridization and immunoautoradiography. The distribution of labelling for TH protein and TH mRNA was almost superimposable and close to that of DAT mRNA in mesencephalic neurons. Lower values of cellular expression in TH protein, TH mRNA and DAT mRNA were observed in the lateral part of the SNC compared to the other subregions. TH and DAT expression were correlated in SNC but not in VTA. Indeed DA cells in this region expressed low levels of DAT mRNA in comparison to the middle and medial SNC. These results suggest a heterogeneity of DA metabolism among populations of mesencephalic cells. The relative lower expression of the DAT gene in VTA neurons suggests a less efficient dopamine reuptake capacity, which may partly account for the relative sparing of the mesolimbic system reported in Parkinson's disease and MPTP-treated animals.
Animals↗
Distribution of manganese-dependent superoxide dismutase in the human brain.
The distribution of manganese-dependent superoxide dismutase, an enzyme that transforms superoxide radicals into hydrogen peroxide, was studied in the human brain post mortem using a sheep polyclonal antiserum raised against the enzyme from liver mitochondria. One band, corresponding to a protein of 22,000 mol. wt was detected in the human brain by western blot analysis. At the light-microscopy level, a punctate immunostaining was observed in the neuropil and in some but not all, glial and neuronal cell bodies. Electron-microscopy revealed that the staining was exclusively confined to the inner mitochondrial membrane. A heterogeneous distribution of manganese-dependent superoxide dismutase was observed in the human brain. In the forebrain, numerous immunostained neurons were detected in the striatum, thalamus, pallidal complex and the nucleus basalis of Meynert. In the cerebellum, only granular and Purkinje cells were immunostained. Various nuclei from the brainstem displayed superoxide dismutase immunoreactivity, including the cranial nerve nuclei, the nucleus supratrochlearis, the red nucleus, the substantia nigra, the nucleus cuneiformis and subcuneiformis, the nucleus parabigeminal, the nucleus centralis superior, the nucleus supraspinalis, the nucleus of the medullae oblongata and the gigantocellularis nucleus. Large pyramidal neurons containing superoxide dismutase were detected in the CA subsectors, the hilus of the hippocampus and the cerebral cortex. Smaller immunostained neurons were also observed in layers I, IV and VI of all cortical regions studied. The distribution of immunostained glial cells was more limited, and restricted to the internal and external capsules, the hypothalamus, the red nucleus, the pyramidal white matter and surrounding areas, the cerebral cortex and the sub-ependymal layer, the alveus and the stratum oriens of the hippocampus. This heterogeneous but not ubiquitous distribution of cells expressing manganese-dependent superoxide dismutase suggests that not all cells in the human brain are protected to the same extent against the deleterious effects of superoxide.
Aged↗
Immunohistochemical study of catechol-O-methyltransferase in the human mesostriatal system.
The cellular localization of catechol-O-methyltransferase was analysed in the mesostriatal system of human brain post mortem by means of immunohistochemistry. In the human nigral complex, catechol-O-methyltransferase immunostaining was not detected in melanized dopaminergic neurons, except in the ventral tegmental area and substantia nigra pars lateralis, where few neurons displayed intense immunolabelling. In the striatum, catechol-O-methyltransferase immunostaining was found in numerous cell bodies and in the neuropile. Observations at the electron microscope level revealed that catechol-O-methyltransferase immunoreactivity was present in the cell bodies of neurons and their processes, including the dendritic spines. No catechol-O-methyltransferase immunolabelling was observed in striatal nerve terminals in contact with dendritic spines, indicating that dopaminergic nerve terminals do not exhibit catechol-O-methyltransferase immunoreactivity. Catechol-O-methyltransferase-immunoreactive cell bodies and processes of glial cells were also detected in the striatum. The data suggest that catechol-O-methyltransferase is either not expressed or only slightly expressed by the dopaminergic nigrostriatal neurons, whereas it is clearly present in striatal neurons and glial cells. Thus, the catabolic degradation of striatal released dopamine by its O-methylation may involve postsynaptic neurons rather than dopaminergic presynaptic neurons. The presence of catechol-O-methyltransferase in some dopaminergic neurons of the ventral tegmental area and substantia nigra pars lateralis suggests that methylation of dopamine may occur in these neurons, which may consequently be better protected against dopamine auto-oxidation than those of the substantia nigra pars compacta.
Animals↗
Somatostatin messenger RNA-containing neurons in Alzheimer's disease: an in situ hybridization study in hippocampus, parahippocampal cortex and frontal cortex.
The level of expression of somatostatin messenger RNA-containing neurons in human brain was visualized and quantified by in situ hybridization with a 35S-labelled oligonucleotide complementary to amino acids 96-111 of the preprosomatostatin complementary DNA sequence. The analysis was carried out in the frontal and parahippocampal cortices and hippocampus of six age- and post mortem delay-matched Alzheimer's disease and control brains. By northern blot analysis, in frontal cortex samples, 18S rRNA degradation was identical in control and Alzheimer brains and somatostatin messenger RNAs migrated as a single band of 1 kb. By in situ hybridization, specificity was demonstrated by abolition of the signal using either an excess of unlabelled antisense probe or using a labelled sense probe. Somatostatin messenger RNA-containing neurons displayed a similar regional and subregional distribution in control subjects and patients with Alzheimer's disease, being more abundant in the frontal cortex, followed by the hippocampus and the parahippocampal cortex. An overall reduction of labelled cell density was observed in patients with Alzheimer's disease (frontal cortex gray matter:--41%; white matter:--66%; hippocampus:--44%; parahippocampal cortex white matter:--40%). Due to a great variation between brains, this decrease only reached significance in the parahippocampal cortex (-59%, P < 0.05). A significantly lower level of expression of somatostatin messenger RNA per somatostatinergic cell was observed in the hippocampus of Alzheimer's disease patients (-47%, P < 0.05), but not in frontal cortex gray (-17%) and white (-36%) matter and parahippocampal cortex gray (-42%) and white (-29%) matter. These data are in accordance with the distribution of somatostatin cells as visualized by immunohistochemistry in human brain. They indicate that the ability of cortical cells to express somatostatin messenger RNA is partially preserved in Alzheimer disease brains and that the decrease in the amount of somatostatin messenger RNA per cell is restricted to the hippocampal formation.
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Low affinity nerve growth factor receptor, adrenal transplant and Parkinson's disease.
Immunohistochemistry of low-affinity nerve growth factor receptor (LNGFR) was performed postmortem in the striatum and the adrenal gland of a parkinsonian patient with an adrenal to brain transplantation. Few LNGFR-positive fibers were observed in the necrotic graft. By contrast numerous immunostained fibers were detected in a restricted zone of the host striatum adjacent to the graft, corresponding to a selective zone of sprouting of tyrosine hydroxylase-positive fibers. This suggests that nerve growth factor or related growth factors may promote sprouting of catecholaminergic fibers in the host striatum.
Adrenal Medulla↗
Autoradiographic study of [125I]epidermal growth factor-binding sites in the mesencephalon of control and parkinsonian brains post-mortem.
Epidermal growth factor (EGF) is assumed to act as a neurotrophic factor on dopaminergic nigrostriatal neurons in cell cultures and animal brain. This led us to consider its possible role in the pathophysiology of Parkinson's disease. An autoradiographic study of the distribution of EGF-binding sites was performed in the mesencephalon of controls and patients with Parkinson's disease, a neurodegenerative disease associated with dramatic damage to the mesostriatal dopaminergic neurons. Scatchard analysis revealed a single type of binding sites with a high affinity constant, in the various mesencephalic dopaminergic areas examined. The characteristics and density of [125I]EGF-binding sites were similar in controls and parkinsonian patients. This suggests that EGF receptors in the mesencephalon are unaffected in Parkinson's disease and may therefore contribute to the increased activity and survival of the remaining dopaminergic neurons.
Autoradiography↗
Differential vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine of dopaminergic and cholinergic neurons in the monkey mesopontine tegmentum.
Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra and, in the most severe cases, by degeneration of mesopontine cholinergic neurons. In a monkey model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine we report that, despite a severe loss of dopaminergic neurons, in the mesopontine tegmentum cholinergic neurons are preserved in the same region. This suggests that the loss of mesopontine cholinergic neurons in parkinsonian patients may represent an end-stage degenerative process, the cause of which may be independent of the mechanism of dopaminergic cell death.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗