PubMed Health⌕ Search

Biomedical subjects

B Ghetti

Publications and source records attributed to B Ghetti.

At least 73 records · Page 4Linked to original sources
PubMed1997

Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments.

Neurofibrillary lesions made of hyperphosphorylated microtubule-associated protein tau constitute not only one of the defining neuropathological features of Alzheimer disease but also are present in a number of other neurodegenerative diseases with dementia. Here we describe a novel autosomal dominant disease named familial "multiple system tauopathy with presenile dementia," which is characterized by abundant fibrillary deposits of tau protein in both neurons and glial cells. There are no detectable deposits of beta-amyloid. The tau deposits are in the form of twisted filaments that differ in diameter and periodicity from the paired helical filaments of Alzheimer disease. They are stained by both phosphorylation-independent and -dependent anti-tau antibodies. Moreover, tau immunoreactivity coexists with heparan sulfate in affected nerve and glial cells. Tau protein extracted from filaments of familial multiple system tauopathy with presenile dementia shows a minor 72-kDa band and two major bands of 64 and 68 kDa that contain mainly hyperphosphorylated four-repeat tau isoforms of 383 and 412 amino acids.

Aged↗
PubMed1997

A possible role for tyrosine kinases in the regulation of the neuronal dopamine transporter in mouse striatum.

The present investigation was undertaken to test the hypothesis that a reduction in the activity of protein tyrosine kinases would result in an alteration in dopamine transport. Genistein, a broad-spectrum inhibitor of protein tyrosine kinases, inhibited dopamine uptake into mouse striatal homogenates with an IC50 of 18 microM. The inhibition by genistein was rapid, reversible and somewhat selective, in that genistein did not inhibit the uptake of choline or GABA under similar conditions. Kinetic analyses indicated that genistein was a non-competitive inhibitor. Another protein tyrosine kinase inhibitor, tyrphostin 23, also inhibited transport but was significantly less potent than genistein. Tyrphostin 25 and lavendustin A were without major effect on dopamine uptake. In addition, the inactive structural analog of genistein, genistein, had no significant effect on dopamine uptake. The inhibition of dopamine transport by 50 microM genistein was accompanied by a reduction in the level of a 110-kDa band of tyrosine phosphoprotein. It is suggested that protein tyrosine kinases play a role in the cascade of events which ultimately lead to regulation of neuronal dopamine transport.

Animals↗
PubMed1997

Decreased IGF-I gene expression during the apoptosis of Purkinje cells in pcd mice.

Insulin-like growth factor I (IGF-I) plays a potential functional role in cerebellar development in the rat, as indicated by its spatio-temporally coordinated expression with the IGF-I receptor (IGFR-I), IGF binding protein (IGFBP) 2 and 5 during the postnatal critical growth period. Although IGF-I promotes the survival of cultured cerebellar neurons, its role during cerebellar development in vivo is unclear. Growth factor deprivation has been shown to trigger apoptosis, the developmental cell death which, if abnormal, may lead to various pathological states. To understand the involvement of IGF-I in Purkinje cell survival, we examined mRNA expression of IGF-I, IGFR-I, IGFBP 2 and 5 in the Purkinje cell degeneration (pcd) mice. During pcd cerebellar development, Purkinje cells rapidly degenerate leading to their almost complete depletion by adult life. IGF system mRNA expression was studied during Purkinje cell death in the pcd mutants (pcd/pcd) at postnatal day (D) 11, 17, 24 and adult. At D11 and D17, no significant difference of the IGF-I system mRNA expression was observed between the normal and pcd/pcd cerebellum. At D24, a significant decrease of IGF-I mRNA was found in the apoptotic Purkinje cells in the pcd/pcd cerebellum, which was accompanied by a severe astrogliosis and activation of astrocytic IGF-I expression. In the adult pcd/pcd cerebellum, with few Purkinje cells remaining, many granule cells underwent apoptosis. In conclusion, decreased IGF-I mRNA expression was correlated with Purkinje cell apoptosis in pcd cerebellum. Whether the decrease of IGF-I mRNA expression is the cause or result of the Purkinje cell degeneration needs to be further elucidated.

Animals↗
PubMed1997

Atrophy and loss of dopaminergic mesencephalic neurons in heterozygous weaver mice.

The phenotypic effect of the weaver mutation in the ventral midbrain of homozygous mutants is associated with the progressive loss of dopaminergic neurons. To discover whether the number of mesencephalic dopaminergic cells is altered in weaver heterozygotes (wv/+), we studied mice between 20 and 365 days of age. We counted tyrosine hydroxylase (TH)-immunopositive cells in the substantia nigra (SN), retrorubral nucleus (RRN), and ventral tegmental area (VTA), and measured cross-sectional areas of neuronal somata in the SN of wv/+ and age-matched wild-type controls (+/+). The number of TH-positive cells in the wv/+ ventral midbrain was on average 13% lower than normal. Cell loss was detected selectively in the SN (12%) and VTA (23%). The areas of somatic profiles in the wv/+ nigral neurons were on average reduced by 9.8%. The neuronal losses in the SN and VTA correlated with a 13.8% reduction in dopamine level in the ventral striatum in wv/+ mice at 14-16 months of age. Our findings imply that a single dose of the weaver gene in the mouse is associated with cellular damage leading to a chronic deficiency in the mesostriatal dopaminergic system.

Alleles↗
PubMed1997

In vitro evidence that the reduction in mesencephalic dopaminergic neurons in the weaver heterozygote is not due to a failure in target cell interaction.

The murine weaver (wv) mutation is characterized by a genetically determined loss of several neuronal populations, which include the nigrostriatal dopaminergic neurons. Animals homozygous for the wv gene exhibit marked deficits in dopaminergic morphological and neurochemical parameters. The wv gene shows incomplete dominance in that heterozygous (wv/+) mice exhibit moderate reductions in midbrain dopaminergic neuron number. It is unclear whether the dopaminergic neuronal loss in homozygous and heterozygous animals results from an effect of the wv gene solely on the dopaminergic neurons or is due to a failure of interaction of dopaminergic neurons with target cells of the striatum. This issue has been addressed utilizing three-dimensional reaggregate tissue cultures to determine whether the wv gene acts directly on the mesencephalic dopaminergic neurons. Embryonic mesencephalon and striatum from wv/+ and wild-type (+/+) brains were dissociated and the cells recombined into four mesencephalic-striatal aggregate combinations: (1) mesencephalic(+/+)-striatal(+/+)aggregates; (2) mesencephalic(wv/+)-striatal(wv/+)aggregates; (3) mesencephalic(wv/+)-striatal(+/+)aggregates; and (4) mesencephalic(+/+)-striatal(wv/+)aggregates. At 29 days and 57 days of culture, the number of dopaminergic neurons and dopamine content from mesencephalic-striatal aggregates consisting of mixed genotype or from only wv/+ tissue were quantitated and compared with that from mesencephalic-striatal cultures prepared from +/+ tissue alone. At both culture time points, aggregates containing wv/+ mesencephalon coaggregated with either wv/+ or +/+ striatum contained fewer dopaminergic neurons than mesencephalic-striatal cultures composed of only +/+ cells. Coaggregation of +/+ mesencephalon with wv/+ striatum did not have a detrimental effect on dopaminergic cell number. The findings demonstrate that the difference in the number of mesencephalic dopaminergic neurons between wv/+ and +/+ animals seen in vivo can be reproduced in three-dimensional reaggregate culture. Since the coculture of +/+ striatum with wv/+ mesencephalon did not appear to rescue wv/+ dopaminergic neurons in the aggregates as compared to wv/+ striatum and, wv/+ striatum proved to be a perfectly adequate target for +/+ mesencephalic dopaminergic neurons, it appears that the effect of the wv gene is on the dopaminergic neurons themselves.

Animals↗
PubMed1997

Subacute sclerosing panencephalitis manifesting as viral retinitis: clinical and histopathologic findings.

PURPOSE AND METHODS: To describe the clinical and histopathologic features of a patient with viral retinitis secondary to subacute sclerosing panencephalitis. RESULTS: The patient was a human immunodeficiency virus-negative intravenous drug abuser with an acute retinitis that later progressed to encephalitis despite aggressive treatment for possible viral, protozoal, bacterial, and rickettsial infections. The patient had many of the characteristic findings of subacute sclerosing panencephalitis, including a history of measles in early childhood, myoclonus, periodic complexes on electroencephalographic testing, persistently elevated serum and cerebrospinal fluid antimeasles immunoglobulin G (IgG) titers, and a cerebrospinal fluid oligoclonal IgG gammopathy. Ultrastructural examination demonstrated numerous filamentous microtubular intranuclear viral inclusions in the nuclear layers of the retina consistent with the measles virus. This case is unusual in that our patient developed subacute sclerosing panencephalitis later in life and because there was an 8-year period between presumed viral infections in the two eyes. CONCLUSIONS: An acute retinitis in an intravenous drug abuser is not always caused by human immunodeficiency virus-related infections; not all viral retinitis responds to therapy; and mortality as well as the usual morbidity may be associated with viral retinitis. One might consider the diagnosis of subacute sclerosing panencephalitis in a young person with an acute retinitis with little or no vitreal inflammation and lack of response to anticytomegalovirus and antitoxoplasmosis therapy.

Adult↗
PubMed1997

Gerstmann-Sträussler-Scheinker disease with the PRNP P102L mutation and valine at codon 129.

The most common mutation causing Gerstmann-Sträussler-Scheinker (GSS) disease is P102L in the prion protein. Previously, this mutation has only been found in coupling with methionine at residue 129. We describe a patient with GSS disease in whom the P102L mutation is in coupling with valine at residue 129. The clinical presentation in P102L-V129 differs greatly from that seen in P102-M129 patients.

Adult↗
PubMed1997

Familial multiple-system tauopathy with presenile dementia is localized to chromosome 17.

An autosomal dominant presenile dementia affecting 39 individuals in a seven-generation, 383-member pedigree has been studied at Indiana University. In the affected members of this family, clinical symptoms occurred early in life, with an average age at onset of 48.8 years. The presenting clinical features include disequilibrium, neck stiffness, dysphagia, and memory loss. As the disease progresses, further cognitive decline, superior-gaze palsy, and dystaxia also are observed. The average duration from onset of symptoms to death is approximately 10 years. Neuropathologic studies of nine affected individuals showed neuronal loss in several areas of the CNS, as well as argentophilic tau-immunopositive inclusions in neurons and in oligodendroglia. A limited genomic screen by use of DNA samples from 28 family members localized the gene for this disorder to a 3-cM region on chromosome 17, between the markers THRA1 and D17S791. The gene for tau also was analyzed, through samples from the family.

Adult↗
PubMed1997

Neuropsychological function in patients with Gerstmann-Sträussler-Scheinker disease from the Indiana kindred (F198S).

Three patients with Gerstmann-Sträussler-Scheinker disease (GSS) caused by a serine-for-phenylalanine substitution at codon 198 of the prion protein gene (PRNP) were compared to 9 age- and education-matched non-mutation-carriers from the same large Indiana kindred (GSS-IK) on a comprehensive neuropsychological test battery. Clinically significant impairments in intelligence, secondary memory, attention and cognitive processing speed, executive ability, and manual motor skills were noted in 2 patients. The wide range and the severity of the cognitive deficits indicated generalized cerebral dysfunction consistent with global dementia. One patient, symptomatic for less than 1 year, had more selective deficits involving memory, motor skills, and verbal fluency, suggesting early subcortical involvement.

Adult↗
PubMed1997

In situ hybridization analysis of Girk2 expression in the developing central nervous system in normal and weaver mice.

A mutation in the gene Girk2 that encodes an inwardly rectifying potassium channel is the genetic defect causing the behavioral and pathologic abnormalities of the weaver mutant mouse. Of the pathologic abnormalities, the best studied is the neuronal degeneration that occurs in the cerebellar cortex and in the midbrain dopaminergic neurons. A detailed characterization of the topographic and temporal expression of Girk2 is fundamental to elucidate the mechanisms underlying neurodegeneration in these mutant mice. In this study we utilized in situ hybridization to determine the expression of Girk2 mRNA during prenatal and postnatal development in the murine central nervous system (CNS). Girk2 expression was seen in multiple regions of embryonic CNS including the cerebellum and midbrain. During postnatal development, the highest expression was seen in the cerebellum, midbrain and hippocampus. However, since the developing cerebellum undergoes significant neuronal loss due to the degeneration of granule cell precursors, Girk2 mRNA expression in this area decreases progressively.

Animals↗
PubMed1997

Diverse cell death pathways result from a single missense mutation in weaver mouse.

Neuronal death affects selectively granule cell precursors of the cerebellum and the dopaminergic neurons of midbrain in the weaver mutant mouse. The weaver phenotype is associated with a missense mutation in the gene coding for the GIRK2 potassium channel, which results in chronic depolarization. Using DNA gel electrophoresis, electron microscopy (EM), the in situ end-labeling (ISEL) technique at the light and EM level, and immunohistochemistry for apoptosis-related proteins c-Jun and proliferating cell nuclear antigen (PCNA), we have investigated the mechanisms of cell death in cerebellum and substantia nigra. Between postnatal day P1 and P21, in the external germinal layer of the cerebellum, most degenerating granule cell precursors were found to aggregate to form clusters. Degenerating cells exhibited strong nuclear staining for ISEL, c-Jun, and PCNA and had a typical apoptotic morphology by EM. Increased c-Jun and ISEL staining were also occasionally seen in Purkinje cells. Between P14 and P21, when dopaminergic neurons start to degenerate, staining for ISEL, c-Jun, and PCNA in weaver substantia nigra was the same as in controls. By EM, however, we found only in weaver mice numerous dopaminergic cells that showed extensive vacuolar and autophagic changes of cytoplasm, preservation of membrane and organelle integrity, and absence of chromatin condensation or DNA fragmentation by EM-ISEL. The combination of vacuolar and autophagic changes identifies a novel type of non-necrotic, nonapoptotic cell death. After biochemical analysis of DNA, a clear-cut laddering, suggestive of oligonucleosomal fragmentation, was present in samples from weaver cerebellum. Cell death diversity appears to be influenced by specific features of target cells. These findings may be relevant for understanding the mechanisms of cell death in neurodegenerative diseases.

Animals↗
PubMed1996

Phenotypic effects of the weaver gene are evident in the embryonic cerebellum but not in the ventral midbrain.

Degeneration of neurons in two structures, the cerebellum and the dopaminergic neurons in the ventral midbrain, is a well characterized action of the weaver gene. In order to see whether the gene has effects prenatally, both the cerebellum and the ventral midbrain were examined in mouse embryos genotyped for the weaver gene (wv, Girk2) on day E19. Anatomically matched sections of the midline cerebellar vermis were quantitatively analyzed 2 h after the dams were given a single injection of [3H]thymidine. A gene-dose effect was seen in the retardation of fissure development. This was more pronounced in homozygotes (wv/wv) and less so in heterozygotes (wv/+) when compared with wild type controls (+/+). Quantitative measures of the following features showed stepwise differences between genotypes so that the wv/wv are most affected and wv/+ are somewhat affected compared with +/+: surface length of the midline vermis, area of the entire midline vermis and the external germinal layer (egl), total number of cells in the egl, [3H]thymidine-labeled and -unlabeled egl cells, cells in the Purkinje cell layer, cells in the region of the deep nuclei, [3H]thymidine-labeled cells in the Purkinje cell layer (presumptive proliferating Bergmann glia), and [3H]thymidine-labeled cells in the region of the deep nuclei. In contrast to the obvious phenotypic effects of wv in the embryonic cerebellum, qualitative immunocytochemical examination of tyrosine hydroxylase staining in the ventral midbrains of the same embryos showed that the position and density of the presumptive dopaminergic neurons was similar in all genotypes.

Animals↗
PubMed1996

The weaver mutation changes the ion selectivity of the affected inwardly rectifying potassium channel GIRK2.

The weaver mutation in mice has recently been identified as a single base-pair mutation in the Girk2 gene, which encodes a G-protein-activated inwardly rectifying potassium channel, GIRK2. The mutation results in a Gly to Ser substitution at residue 156, in the putative pore-forming region of the potassium channel. In the present study, we used Xenopus oocytes to express mutant GIRK2, and to characterize the effects of the mutation on the channel. The mutation results in a loss of the normal high selectivity for K+ over Na+, with little effect on other channel properties such as activation by the mu opioid receptor. The resulting increase in basal Na+ permeability causes a marked depolarization of oocytes expressing the mutant GIRK2 protein. This result was observed even when the mutant GIRK2 was coexpressed with GIRK1, a situation more analogous to that seen in vivo. Thus, the increased Na+ permeability and resulting depolarization may contribute to the pathology of cerebellar granule cells and substantia nigra dopaminergic neurons observed in the weaver mice.

Analgesics↗
PubMed1996

PrP27-30 is a normal soluble prion protein fragment released by human platelets.

Prion diseases are neurodegenerative disorders characterized by the accumulation of abnormal isoforms of prion protein (PrPSc) in the central nervous system. PrPSc isoforms differ from their normal homologue (PrPC), in that they possess increased beta-sheet conformation, are partially protease resistant and may be associated with amyloid deposition. Amyloid proteins are thought to derive from soluble precursors or fragments thereof, present in biological fluids, which in the disease state undergo conformational change leading to aggregation and deposition in target tissues. We report here that platelets carry PrP mRNA and release PrPC, a sialoglycoprotein bound to the cell surface by a glycosylphosphatidylinositol (GPI) anchor. Soluble PrPC, and a N-terminal truncated PrPC isoform starting at position 90 are secreted by resting and agonist-stimulated platelets and are detectable after partial deglycosylation of releasates. N-terminal sequence analysis of the soluble 27-30 kDa isoform, GQGGGTHSQ(W)NKP, revealed homology to scrapie PrP27-30, the protease resistant core derived from PrPSc. These findings indicate that in addition to PrPC, platelets process a soluble PrP27-30 isoform. Whether this isoform can be converted in scrapie PrP27-30 remains to be determined.

Amino Acid Sequence↗
PubMed1996

Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP.

Deposition of PrP amyloid in cerebral vessels in conjunction with neurofibrillary lesions is the neuropathologic hallmark of the dementia associated with a stop mutation at codon 145 of PRNP, the gene encoding the prion protein (PrP). In this disorder, the vascular amyloid in tissue sections and the approximately 7.5-kDa fragment extracted from amyloid are labeled by antibodies to epitopes located in the PrP sequence including amino acids 90-147. Amyloid-laden vessels are also labeled by antibodies against the C terminus, suggesting that PrP from the normal allele is involved in the pathologic process. Abundant neurofibrillary lesions are present in the cerebral gray matter. They are composed of paired helical filaments, are labeled with antibodies that recognize multiple phosphorylation sites in tau protein, and are similar to those observed in Alzheimer disease. A PrP cerebral amyloid angiopathy has not been reported in diseases caused by PRNP mutations or in human transmissible spongiform encephalopathies; we propose to name this phenotype PrP cerebral amyloid angiopathy (PrP-CAA).

Adult↗
PubMed1996

Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease.

We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methionine/valine polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to "type 1" protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the "type 2" protease-resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob disease.

Adult↗