Genetic complexity and Parkinson's disease.
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Adult↗
Biomedical subjects
Y Agid
Publications and source records attributed to Y Agid.
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.
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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.
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An immunocytochemical study of a G-protein-gated inward rectifier K+ channel (GIRK2) in the weaver mouse mesencephalon.
It has been suggested that a mutation in a G-protein-gated inward rectifier K+ channel (GIRK2) is responsible for inducing cell death in the cerebellum of homozygous weaver (wv/wv) mutant mice. These mice also display a progressive, massive loss of mesencephalic dopaminergic neurones. Using an immunocytochemical method, we detected GIRK2-positive cell bodies and fibres in the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) of control (+/+) mice. Cell counts of both GIRK2- and tyrosine hydroxylase (TH)-positive neurones demonstrated a marked loss of SNC cell bodies, especially in 12-month-old (12M) wv/wv mice. A considerable proportion of GIRK2-positive cell bodies were preserved, however. In addition, no loss of GIRK2-positive neurones was observed in the VTA of 12M wv/wv mice, despite of a significant reduction in TH-positive cell bodies. These results suggest that expression of the mutated channel is not a sufficient condition to induce cell death in the ventral mesencephalon of the wv/wv mice.
Aging↗
Absence of neurotoxicity of chronic L-DOPA in 6-hydroxydopamine-lesioned rats.
We investigated the effects of 6 months' oral treatment with L-dihydroxy-phenylalanine (L-DOPA)/carbidopa on the remaining dopaminergic neurones of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) of rats with moderate or severe 6-hydroxydopamine (6-OHDA)-induced lesions and sham-operated animals. Using a radioimmunohistochemical method we counted tyrosine hydroxylase (TH)-radioimmunoreactive cells in the SNC and the VTA in emulsion-coated sections and measured the remaining surface area of both structures on autoradiograms. The sole difference observed was a significant increase of the remaining surface area of TH radioimmunolabelling in the SNC of moderately lesioned rats treated with L-DOPA/carbidopa compared with the untreated animals, while the rest of the parameters recorded, in both structures and groups of animals, were unchanged. This suggest that in vivo, this treatment is not toxic either to healthy dopaminergic neurones of the ventral mesencephalon or to those surviving after a 6-OHDA lesion.
Animals↗
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.
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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.
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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.
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What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study.
BACKGROUND: The presentation of symptoms for multiple system atrophy (MSA) varies. Because there are no specific markers for its clinical diagnosis, the diagnosis rests on the results of the neuropathologic examination. Despite several clinicopathologic studies, the diagnostic accuracy for MSA is unknown. OBJECTIVES: To determine the accuracy for the clinical diagnosis of MSA and to identify, as early as possible, those features that would best predict MSA. DESIGN: One hundred five autopsy-confirmed cases of MSA and related disorders (MSA [n=16], non-MSA [n=89]) were presented as clinical vignettes to 6 neurologists (raters) who were unaware of the study design. Raters identified the main clinical features and provided a diagnosis based on descriptions of the patients' first and last clinic visits. METHODS: Interrater reliability was evaluated with the use of kappa statistics. Raters' diagnoses and those of the primary neurologists (who followed up the patients) were compared with the autopsy-confirmed diagnoses to estimate the sensitivity and positive predictive values at the patients' first and last visits. Logistic regression analysis was used to determine the best predictors to diagnose MSA. RESULTS: For the first visit (median, 42 months after the onset of symptoms), the raters' sensitivity (median, 56%; range, 50%-69%) and positive predictive values (median, 76%; range, 61%-91%) for the clinical diagnosis of MSA were not optimal. For the last visit (74 months after the onset of symptoms), the raters' sensitivity (median, 69%; range, 56%-94%) and positive predictive values (median, 80%; range, 77%-92%) improved. Primary neurologists correctly identified 25% and 50% of the patients with MSA at the first and last visits, respectively. False-negative and -positive misdiagnoses frequently occurred in patients with Parkinson disease and progressive supranuclear palsy. Early severe autonomic failure, absence of cognitive impairment, early cerebellar symptoms, and early gait disturbances were identified as the best predictive features to diagnose MSA. CONCLUSIONS: The low sensitivity for the clinical diagnosis of MSA, particularly among neurologists who followed up these patients in the tertiary centers, suggests that this disorder is underdiagnosed. The misdiagnosis of MSA is usually due to its confusion with Parkinson disease or progressive supranuclear palsy, thus compromising the research on all 3 disorders.
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Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families.
Charcot-Marie-Tooth disease can be inherited either autosomal dominantly or recessively or linked to the X chromosome. X-linked dominant Charcot-Marie-Tooth disease (CMTX) is a sensorimotor peripheral neuropathy in which males have usually more severe clinical symptoms and decreased nerve conduction velocities than do females. CMTX is usually associated with mutations in exon 2 of the connexin 32 (Cx32) gene. DNA from 35 unrelated CMT patients, without the 17p11.2 duplication, but with median nerve conduction between 30 and 40 m/s, were tested for the presence of Cx32 mutations. The entire coding sequence of the Cx32 gene was explored using a rapid nonradioactive technique to detect single-strand conformation polymorphisms (SSCP) on large PCR fragments. Thirteen abnormal SSCP profiles were detected and characterized by sequencing. In addition, systematic sequencing of the entire Cx32 coding region in the remaining index cases revealed another mutation that was not detected by SSCP. A total of 14 mutations were found, five of which were not previously reported. These results demonstrate the high frequency (40%) of mutations in the coding region of the Cx32 gene in CMT patients with intermediate MNCV, without 17p11.2 duplications. Most of these mutations (93%) can be detected by SSCP.
Amino Acid Sequence↗
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.
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Urinary disturbances in striatonigral degeneration and Parkinson's disease: clinical and urodynamic aspects.
Although urinary disturbances are more frequent in multiple system atrophy (MSA) than in Parkinson's disease (PD), the striatonigral degeneration (SND) type of MSA is difficult to distinguish from PD, especially when the latter is associated with orthostatic hypotension or urinary symptoms. The pattern of urinary symptoms and urodynamic dysfunction was analyzed in 15 SND and 35 PD patients with urinary complaints. In SND, dysuria with or without chronic retention, frequently associated with a hypoactive detrusor and low urethral pressure, permitted early and reliable diagnosis. In PD, urgency to void, with or without difficulty voiding, but without chronic retention, associated with detrusor hyperreflexia and normal urethral sphincter function, predominated. In clinical practice, the study of urinary symptoms and bladder function may help to distinguish SND from PD in patients with urinary disturbances.
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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.
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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↗
Linkage disequilibrium between the spinocerebellar ataxia 3/Machado-Joseph disease mutation and two intragenic polymorphisms, one of which, X359Y, affects the stop codon.
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Brain↗
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↗
An immunocytochemical study on the distribution of two G-protein-gated inward rectifier potassium channels (GIRK2 and GIRK4) in the adult rat brain.
G-protein-gated inward rectifier potassium channels mediate the synaptic actions of numerous neurotransmitters in the mammalian brain, and were recently shown to be candidates for genetic mutations leading to neuronal cell death. This report describes the localization of G-protein-gated inward rectifier potassium channel-2 and G-protein-gated inward rectifier potassium channel-4 proteins in the rat brain, as assessed by immunocytochemistry. G-protein-gated inward rectifier potassium channel-2 immunoreactivity was widely distributed throughout the brain, with the strongest staining seen in the hippocampus, septum, granule cell layer of the cerebellum, amygdala and substantia nigra pars compacta. In contrast, G-protein-gated inward rectifier potassium channel-4 immunoreactivity was restricted to some neuronal populations, such as Purkinje cells and neurons of the globus pallidus and the ventral pallidum. The presence of G-protein-gated inward rectifier potassium channel-2 immunoreactivity in substantia nigra pars compacta dopaminergic neurons was confirmed by showing its co-localization with tyrosine hydroxylase by double immunocytochemistry, and also by selectively lesioning dopaminergic neurons with the neurotoxin 6-hydroxydopamine. At the cellular level both proteins were localized in neuronal cell bodies and dendrites, but clear differences were seen in the degree of dendritic staining among neuronal groups. For some neuronal groups the staining of distal dendrites (notably dendritic spines) was strong, while for others the cell body and proximal dendrites were preferentially labelled. In addition, some of the results suggest that G-protein-gated inward rectifier potassium channel-2 protein could be localized in distal axonal terminal fields. A knowledge of the distribution of G-protein-gated inward rectifier potassium channel proteins in the brain could help to elucidate their physiological roles and to evaluate their potential involvement in neurodegenerative processes in animal models and human diseases.
Animals↗
Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion.
The gene for spinocerebellar ataxia 7 (SCA7) has been mapped to chromosome 3p12-13. By positional cloning, we have identified a new gene of unknown function containing a CAG repeat that is expanded in SCA7 patients. On mutated alleles, CAG repeat size is highly variable, ranging from 38 to 130 repeats, whereas on normal alleles it ranges from 7 to 17 repeats. Gonadal instability in SCA7 is greater than that observed in any of the seven known neuro-degenerative diseases caused by translated CAG repeat expansions, and is markedly associated with paternal transmissions. SCA7 is the first such disorder in which the degenerative process also affects the retina.
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