Biomedical subjects

M G Spillantini

Publications and source records attributed to M G Spillantini.

At least 37 records · Page 2Linked to original sources

PubMed2000

Progress in hereditary tauopathies: a mutation in the Tau gene (G389R) causes a Pick disease-like syndrome.

We describe the clinical and pathologic phenotypes of the G389R mutation in exon 13 of the Tau gene. Progressive aphasia and memory disturbance are the initial signs and begin in the fourth or fifth decade of life, followed by apathy, indifference, hyperphagia, rigidity, pyramidal signs and dementia. Death occurs after two to five years. Magnetic resonance imaging and neuropathologic studies show frontal and temporal atrophy. Pick body-like and axonal filamentous inclusions found in the neocortex and subcortical white matter, respectively, are tau immunoreactive. Immunoblot analysis of sarkosyl-insoluble tau shows two major bands of 60 and 64 kDa that, upon dephosphorylation, resolve into four bands of three- and four-repeat isoforms. Isolated tau filaments are often straight and occasionally twisted. Recombinant mutant tau protein shows a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. The present findings indicate that the G389R mutation in Tau can cause a dementia similar to that in Pick's disease.

Adult↗

PubMed2000

Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Their relevance for understanding the neurogenerative process.

Tau is a microtubule-associated protein that binds to microtubules and promotes microtubule assembly. Six tau isoforms are produced in adult human brain by alternative mRNA splicing from a single gene. Inclusion of a 31 amino acid repeat encoded by exon 10 of the tau gene gives rise to the three isoforms with four microtubule-binding repeats each. The other three tau isoforms have three repeats each. Abundant neurofibrillary lesions made of tau protein constitute a defining neuropathological characteristic of Alzheimer's disease. Filamentous tau protein deposits are also the defining characteristic of other neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. It is well established that the distribution of tau pathology correlates with the presence of symptoms of disease. However, until recently, there was no genetic evidence linking tau to neurodegeneration. This has now changed with the discovery of more than 15 mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The new work has shown that dysfunction of tau protein causes neurodegeneration.

Adult↗

PubMed2000

A novel mutation at position +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto)

Exonic and intronic mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe a new mutation, consisting of a C-to-T transition at position +12 of the intron following exon 10 of the tau gene in the Kumamoto pedigree, showing frontotemporal dementia. The mutation caused a marked reduction in melting temperature of the tau exon 10-splicing regulatory element RNA and a large increase in exon 10-containing transcripts. Brain tissue from affected individuals showed an abnormal preponderance of exon 10-containing transcripts that was reflected at the protein level by an overproduction of tau isoforms with four microtubule-binding repeats. Immunostaining revealed the presence of tau aggregates in degenerating neurons and glial cells. Isolated tau filaments had a twisted ribbon-like morphology and were made of hyperphosphorylated four-repeat tau isoforms. The additional mutation located dose to the splice-donor site of the intron following exon 10 of the tau gene supports the view that intronic mutations exercize their pathogenic effect by destabilizing RNA secondary structure.

Brain↗

PubMed1999

Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17.

Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Intronic mutations and some missense mutations increase splicing in of exon 10, leading to an increased ratio of four-repeat to three-repeat tau isoforms. Secondary structure predictions have led to the proposal that intronic mutations and one missense mutation destabilize a putative RNA stem-loop structure located close to the splice-donor site of the intron after exon 10. We have determined the three-dimensional structure of this tau exon 10 splicing regulatory element RNA by NMR spectroscopy. We show that it forms a stable, folded stem-loop structure whose thermodynamic stability is reduced by frontotemporal dementia and parkinsonism linked to chromosome 17 mutations and increased by compensatory mutations. By exon trapping, the reduction in thermodynamic stability is correlated with increased splicing in of exon 10.

Base Sequence↗

PubMed1999

Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition.

Mechanisms for selective targeting to unique subcellular sites play an important role in determining the substrate specificities of protein kinases. Here we show that stress-activated protein kinase-3 (SAPK3, also called ERK6 and p38gamma), a member of the mitogen-activated protein kinase family that is abundantly expressed in skeletal muscle, binds through its carboxyl-terminal sequence -KETXL to the PDZ domain of alpha1-syntrophin. SAPK3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the PDZ domain of alpha1-syntrophin. In skeletal muscle SAPK3 and alpha1-syntrophin co-localize at the neuromuscular junction, and both proteins can be co-immunoprecipitated from transfected COS cell lysates. Phosphorylation of a PDZ domain-containing protein by an associated protein kinase is a novel mechanism for determining both the localization and the substrate specificity of a protein kinase.

Amino Acid Sequence↗

PubMed1999

Phenotypic variation in hereditary frontotemporal dementia with tau mutations.

Several mutations in the tau gene have been found in families with hereditary frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17). This study is the first attempt to correlate genotype and phenotype in six families with FTDP-17 with mutations in the tau gene (deltaK280, G272V, P301L, and R406W). We have investigated tau pathology in 1 P301L and 1 R406W patient. The R406W family showed a significantly higher age at onset (59.2 +/- 5.5 years) and longer duration of illness (12.7 +/- 1.5 years) than the families with the other mutations. The six families showed considerable variation in clinical presentation, but none of them had early parkinsonism. Mutism developed significantly later in the R406W family than in the other families. Frontotemporal atrophy on neuroimaging in the R406W family was less severe than in the P301L and deltaK280 families. The P301L brain contained many pretangles in the frontal and temporal cortex, and the dentate gyrus of hippocampus, showing three tau bands (64, 68, and 72 kd) of extracted tau from the frontal cortex. The presence of many neurofibrillary tangles, many diffuse and classic neuritic plaques in the temporal and parietal cortex, and the hippocampus of the same P301L brain correlated with the presence of four sarkosyl-insoluble (60, 64, 68, and 72 kd) tau bands. The coexistence of characteristic P301L and Alzheimer pathology in the same brain needs further explanation. The R406W brain showed abundant neurofibrillary tangles in several brain regions, and four tau bands (60, 64, 68, and 72 kd) of extracted tau from these regions. The slower progression of the disease in the R406W family might be explained by the microtubule-binding properties of the mutant protein.

Adult↗

PubMed1999

Microtubule-associated protein tau, heparan sulphate and alpha-synuclein in several neurodegenerative diseases with dementia.

Microtubule-associated protein tau forms neurofibrillary lesions in Alzheimer's disease and several other neurodegenerative disorders, such as Niemann-Pick disease type C, subacute sclerosing panencephalitis, argyrophilic grain disease, myotonic dystrophy and motor neuron disease with neurofibrillary tangles. In this study we have compared the characteristics of tau pathology in these diseases using immunohistochemistry and phosphorylation-dependent and phosphorylation-independent anti-tau antibodies. The pattern of staining for heparan sulphate and alpha-synuclein was also investigated. We show that in all of these diseases tau deposits were stained by all anti-tau antibodies used, with the exception of argyrophilic grains which do not stain with antibody 12E8, confirming our previous findings. Heparan sulphate staining was present to a variable extent in all of these diseases, with the exception of subacute sclerosing panencephalitis, in which no staining was observed. Heparan sulphate staining coexisted with tau staining. In some cases it was more extensive than the tau staining. Alpha-synuclein staining was present in presynaptic terminals with the exception of one case of Alzheimer's disease, in which alpha-synuclein-positive Lewy bodies were observed in the hippocampal formation. These findings indicate that tau deposits are antigenically similar in several neurodegenerative diseases and that tau staining is often associated with heparan sulphate staining, supporting the concept that heparan sulphate may be involved in the assembly of tau protein into filaments.

Adolescent↗

PubMed1999

Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures.

Glucocorticoids are toxic to hippocampal neurons. We report here that the steroid dehydroepiandrosterone protects neurons of primary hippocampal cultures against the toxic effects of corticosterone. Corticosterone (20-500 nM) added for 24h to primary cultures of embryonic day 18 rat hippocampus resulted in significant neurotoxicity. Dissociated cells were grown for at least 10 days, initially in serum-containing medium, but serum was removed before adding steroids for 24 h. Neurotoxicity was measured by counting the number of cells stained either for beta-tubulin III or glial fibrillary acidic protein. Corticosterone-induced toxicity was prevented by co-treatment of the cultures with dehydroepiandrosterone (20-500 nM). Dehydroepiandrosterone on its own had little effect, though the highest concentration used (500 nM) was mildly toxic. Immunohistochemical studies on the nuclear translocation of a range of stress-activated protein kinases showed that stress-activated protein kinases 1, 2, 3 and 4 were all translocated by 10 min exposure to corticosterone (100 nM). Dehydroepiandrosterone (100 nM) attenuated the translocation of stress-activated protein kinase 3, but not the others. These experiments show that dehydroepiandrosterone has potent anti-glucocorticoid actions on the brain, and can protect hippocampal neurons from glucocorticoid-induced neurotoxicity. This protective action may involve stress-activated protein kinase 3-related intracellular pathways, though direct evidence for this has still to be obtained.

Animals↗

PubMed1999

Tau gene mutation in familial progressive subcortical gliosis.

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22. This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias. Some of these kindreds have mutations in the tau gene. We report here that PSG-1 has a tau mutation at position +16 of the intron after exon 10. The mutation destabilizes a predicted stem-loop structure and leads to an over-representation of the soluble four-repeat tau isoforms, which assemble into wide, twisted, ribbon-like filaments and ultimately result in abundant neuronal and glial tau pathology. The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau. The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.

Cerebral Cortex↗

PubMed1999

Tau pathology in a family with dementia and a P301L mutation in tau.

Familial forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have recently been associated with coding region and intronic mutations in the tau gene. Here we report our findings on 2 affected siblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive dementing illness clinically diagnosed as Alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. Autopsy in both cases revealed frontotemporal atrophy and degeneration of basal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene revealed a C to T transition at codon 301, resulting in a Pro to Leu substitution. Widespread neuronal and glial inclusions, neuropil threads, and astrocytic plaques similar to those seen in corticobasal degeneration were labeled with a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes spanning the entire tau sequence. Isolated tau filaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble tau exhibited 2 major bands of 64 and 68 kDa and a minor 72 kDa band, similar to the pattern seen in a familial tauopathy associated with an intronic tau mutation. These pathological tau bands predominantly contained the subset of tau isoforms with 4 microtubule-binding repeats selectively affected by the P301L missense mutation. Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.

Atrophy↗

PubMed1999

Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau.

The tau gene has been found to be the locus of dementia with rigidity linked to chromosome 17. Exonic and intronic mutations have been described in a number of families. Here we describe a P301S mutation in exon 10 of the tau gene in a new family. Two members of this family were affected. One individual presented with frontotemporal dementia, whereas his son has corticobasal degeneration, demonstrating that the same primary gene defect in tau can lead to 2 distinct clinical phenotypes. Both individuals developed rapidly progressive disease in the third decade. Neuropathologically, the father presented with an extensive filamentous pathology made of hyperphosphorylated tau protein. Biochemically, recombinant tau protein with the P301S mutation showed a greatly reduced ability to promote microtubule assembly.

Adult↗

PubMed1999

Neuropathological features of frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17): Duke Family 1684.

Frontotemporal dementia with parkinsonism (FTDP-17) is an autosomal dominant disorder that presents clinically with dementia, extrapyramidal signs, and behavioral disturbances in mid-life and progresses to death within 5 to 10 years. Pathologically, the disorder is characterized by variable neuronal loss and gliosis in the frontal and temporal lobes, limbic structures, and the midbrain. Autopsied individuals from some kindreds display abundant neurofibrillary change while others, including a single affected individual from Duke Family 1684, lack distinctive histological features and exhibit only mild neuronal loss and gliosis in limbic structures and subcortical nuclei when examined by routine silver stain. Recently, mutations in the microtubule associated protein tau have been shown to segregate with the disease in this family and in many other affected kindreds. In order to examine the distribution of tau deposits, we performed tau immunohistochemistry, immunoblotting, and immunoelectron microscopy of tau-containing filaments. Immunohistochemistry revealed numerous tau deposits within glial cells and within neurons. Twisted ribbon-like filaments observed by immunoelectron microscopy were immunodecorated with tau AT8 antibody. Sarkosyl-insoluble tau extracted from the hippocampus and cortex migrated as 2 major bands at 64 and 68 kilodaltons and a minor band at 72 kilodaltons, which after alkaline phosphatase treatment appeared to contain mainly tau isoforms with 4 repeats. Furthermore, the ratio of soluble tau with 4 to 3 microtubule-binding repeats was increased. The role of tau mutations in this disorder is discussed in this paper.

Adult↗

PubMed1999

Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits.

Exonic and intronic mutations in Tau cause familial neurodegenerative syndromes characterized by frontotemporal dementia and dysfunction of multiple cortical and subcortical circuits. Here we describe a G389R mutation in exon 13 of Tau. When 38 years old, the proband presented with progressive aphasia and memory disturbance, followed by apathy, indifference, and hyperphagia. Repeated magnetic resonance imaging showed the dramatic progression of cerebral atrophy. Positron emission tomography revealed marked glucose hypometabolism that was most severe in left frontal, temporal, and parietal cortical regions. Rigidity, pyramidal signs and profound dementia progressed until death at 43 years of age. A paternal uncle, who had died at 43 years of age, had presented with similar symptoms. The proband's brain showed numerous tau-immunoreactive Pick body-like inclusions in the neocortex and the fascia dentata of the hippocampus. In addition, large numbers of tau-positive filamentous inclusions were present in axons in the frontal, temporal, and parietal lobes. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa. Upon dephosphorylation, these bands resolved into 4 bands consisting of three- and four-repeat tau isoforms. Most isolated tau filaments were straight and resembled filaments found in Alzheimer disease and some frontotemporal dementias with tau mutations. A smaller number of twisted filaments was also observed. Biochemically, recombinant tau proteins with the G389R mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. Taken together, the present findings indicate that the G389R mutation in Tau can cause a dementing condition that closely resembles Pick's disease.

Adult↗

PubMed1998

Synthetic filaments assembled from C-terminally truncated alpha-synuclein.

Recently two point mutations in the alpha-synuclein gene have been found in familial Parkinson's disease. The characteristic fibrous neuropathological lesions of Parkinson's and other neurodegenerative diseases have been shown to stain strongly with antibodies against alpha-synuclein and extracted filaments have been labelled with anti-alpha-synuclein antibodies. In view of the close involvement of alpha-synuclein filaments with pathology, it was important to establish an in vitro assembly system. We report here that C-terminally truncated recombinant alpha-synuclein readily assembles into filaments resembling those isolated from diseased brain and suggest that truncation by proteolysis may play a role in the pathological process.

Alanine↗

PubMed1998

Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies.

Alpha-synuclein forms the major component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Here we show that alpha-synuclein is also the major component of the filamentous inclusions of multiple system atrophy which comprises several neurodegenerative diseases with a shared filamentous pathology in nerve cells and glial cells. These findings provide an unexpected link between multiple system atrophy and Lewy body disorders and establish that alpha-synucleinopathies constitute a major class of human neurodegenerative disorder.

Adult↗

PubMed1998

Mutation in the tau gene in familial multiple system tauopathy with presenile dementia.

Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease with an abundant filamentous tau protein pathology. It belongs to the group of familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders whose genetic basis is unknown. We now report a G to A transition in the intron following exon 10 of the gene for microtubule-associated protein tau in familial MSTD. The mutation is located at the 3' neighboring nucleotide of the GT splice-donor site and disrupts a predicted stem-loop structure. We also report an abnormal preponderance of soluble tau protein isoforms with four microtubule-binding repeats over isoforms with three repeats in familial MSTD. This most likely accounts for our previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with four repeats. These findings reveal that a departure from the normal ratio of four-repeat to three-repeat tau isoforms leads to the formation of abnormal tau filaments. The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer's disease and other tauopathies.

Adenine↗

PubMed1998

alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.

Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

Autopsy↗

PubMed1998

Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau.

Different mutations in the microtubule-associated tau protein gene have recently been identified in several families with hereditary frontotemporal dementia and Parkinsonism (FTDP-17) linked to chromosome 17q21-22. Some families show neuronal and glial deposits containing hyperphosphorylated tau in several brain regions. We have investigated the presence of tau deposits by using a panel of anti-tau antibodies in three brains of a family with the P301L mutation (HFTD1) and in another family with the G272V mutation (HFTD2) of the tau gene. Numerous intracytoplasmic tau deposits in neurons, glial cells, and neurites were found in hippocampal formation, neocortex, and substantia nigra. These deposits in three patients from HFTD1 consisted of slender twisted filaments 15 nm wide with variable periodicity and a few straight filaments. Tau extracted from these filaments appeared as two major bands of 64 and 68 kd and a minor band of 72 kd that, after alkaline phosphatase treatment, proved to consist mainly of 4-repeat tau isoforms and one of the 3-repeat isoforms. In three patients from HFTD2 numerous Pick-like bodies were present. The conclusion is that the type and distribution of tau deposits in HFTD1 and HFTD2, the physical structure of filaments, and tau isoform composition in HFTD1 differ from Alzheimer's disease and an FTDP-17 family with a V337M mutation in the tau gene.

Aged↗