Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells

Iseki, Eizo; Matsumura, Takehiko; Marui, Wami; Hino, Hiroaki; Odawara, Toshinari; Sugiyama, Naoya; Suzuki, Kyoko; Sawada, Hajime; Arai, Tetsuaki; Kosaka, Kenji

doi:10.1007/s004010000333

Cited by 88 publications

(35 citation statements)

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“…Codon 296 of the tau gene is the only one in which three different mutations have been described (Spillantini et al 2000;Iseki et al 2001;Pastor et al 2001). Clinically, they gave rise to syndromes resembling CBD, PSP or frontotemporal dementia and parkinsonism.…”

Section: Discussionmentioning

confidence: 99%

“…The functional effects of mutations DN296 and N296H were qualitatively and quantitatively similar. Like other tau mutations, N296H is inherited in an autosomal-dominant manner (Iseki et al 2001), whereas DN296 has been described in a homozygous state in some patients (Pastor et al 2001). However, it remains to be seen whether homozygosity for DN296 is always necessary for the clinical expression.…”

Section: Discussionmentioning

confidence: 99%

“…Functionally, it resulted in the increased splicing of exon 10. The deletion mutation DN296 caused severe dementia and atypical progressive supranuclear palsy (PSP) (Pastor et al 2001), whereas the missense mutation N296H gave rise to a clinical phenotype of frontotemporal dementia and parkinsonism (Iseki et al 2001). Here we have analysed the functional effects of mutations DN296 and N296H using microtubule assembly assays, heparin-induced assembly of tau into ®laments and exon trapping.…”

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Functional effects of tau gene mutations ΔN296 and N296H

Yoshida

Crowther

Goedert

2002

Journal of Neurochemistry

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Mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome-17 . Functionally, about half of the known mutations increase the alternative mRNA splicing of exon 10 of the tau gene, resulting in the overproduction of tau isoforms with four microtubule-binding repeats. The other mutations reduce the ability of tau to interact with microtubules, with some mutations also increasing the propensity of tau to assemble into ®laments. Here we have examined the functional effects of the recently described tau gene mutations DN296 and N296H. Both mutations reduced the ability of tau to promote microtubule assembly, without having a signi®cant effect on tau ®lament formation. By exon trapping, they increased the splicing of exon 10. DN296 and N296H thus de®ne a class of tau mutations with effects at both the RNA and the protein level. Keywords: alternative mRNA splicing, frontotemporal dementia and parkinsonism linked to chromosome-17, microtubule assembly, tau ®lament assembly, tau gene.Mutations in the gene encoding the microtubule-associated protein tau cause frontotemporal dementia and parkinsonism linked to chromosome-17 (FTDP-17) (Hutton et al. 1998;Poorkaj et al. 1998;Spillantini et al. 1998). Six tau isoforms are produced in adult human brain by alternative mRNA splicing from a single gene (Goedert et al. 1989). They differ from each other by the presence or absence of 29-or 58-amino-acid inserts located in the amino-terminal half, and an additional 31-amino acid repeat located in the carboxy-terminal half. Inclusion of the latter, which is encoded by exon 10, produces three isoforms with four repeats each; the other three isoforms have three repeats each. The repeats and some adjoining sequences constitute the microtubule-binding domains of tau (Gustke et al. 1994). Similar levels of three-repeat and four-repeat tau isoforms are expressed in normal cerebral cortex (Goedert and Jakes 1990).Functionally, tau mutations can have their primary effect either at the RNA or at the protein level (Goedert 2001). Most mutations in exon 10 and all the intronic mutations in the intron following exon 10 increase the alternative mRNA splicing of exon 10 (Clark et al. 1998; Hutton et al. 1998;Hasegawa et al. 1999). At the protein level, this then leads to a relative overproduction of four-repeat tau (Spillantini et al. 1997). Coding region mutations in exons 9, 12 and 13 of tau impair the ability of tau protein to promote microtubule assembly (Hasegawa et al. 1998;Hong et al. 1998). The same is also true of three missense mutations in exon 10 (DK280, P301L and P301S) (Hasegawa et al. 1998;Bugiani et al. 1999;Rizzu et al. 1999). In addition, a number of coding region mutations promote the ability of tau to assemble into ®laments (Nacharaju et al. 1999;Goedert et al. 1999).Three different mutations have been described in codon 296 of tau. The silent mutation N296N led to a clinical and neuropathological picture resembling corticobasal degeneration (CBD) (Spillantini et al. 2000). Functionall...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Functional effects of tau gene mutations ΔN296 and N296H

Yoshida

Crowther

Goedert

2002

Journal of Neurochemistry

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“…Tau hyper-phosphorylation and abnormal tau deposition in the cytoplasm of neurones and glial cells are major bio-chemical and structural abnormalities in tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD) [3,4,12,21,27,30,54]. In addition, several autosomal dominant inherited syndromes linked to chromosome 17 (FTDP-17) have been described in which the main genetic substrates consist of missense mutations in the coding region, silent mutations, intronic mutations in the splicing regions and single amino acid deletions in the tau gene [1,3,5,8,11,20,23,25,30,34,35,42,50,51,53,55,60]. Clinical manifestations include frontotemporal dementia and parkinsonism, PiD-like, CBD-like, pallido-nigro-luysian degeneration and PSPlike phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation

Ferrer

Pástor

Rey

et al. 2003

Neuropathology Appl Neurobio

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Tau phosphorylation has been examined by immunohistochemistry in the brain of a patient affected with familial tauopathy with progressive supranuclear palsy-like phenotype linked to the delN296 mutation in the tau gene. Phospho-specific tau antibodies Thr181, Ser202, Ser214, Ser396 and Ser422, and antibodies to glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) and to phosphorylated (P) mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), p38 kinase (p38) and GSK-3betaSer9 have been used to gain understanding of the identification of phosphorylation sites, as well as of the specific kinases that regulate tau phosphorylation at those specific sites, in a familial tauopathy. The neuropathological examination disclosed atrophy of the right precentral gyrus and the brainstem. Neurone loss and gliosis were observed in the substantia nigra, several nuclei of the brainstem and diencephalon. Hyper-phosphorylated tau accumulated in neurones with neurofibrillary tangles and in neurones with pretangles in the substantia nigra, locus ceruleus, peri-aqueductal grey matter, reticular formation, motor nuclei of the brainstem, and thalamus, amygdala and hippocampus. tau-immunoreactive astrocytes and, particularly, oligodendrocytes with coiled bodies were widespread in the brainstem, diencephalons, cerebral white matter and cerebral cortex. Increased expression of MAPK/ERK-P, SAPK/JNK-P, p-38-P and GSK-3beta-P was observed in select subpopulations of neurones with neurofibrillary tangles and in neurones with pretangles. MAPK/ERK-P, SAPK/JNK-P, p38-P and GSK-3beta-P were also expressed in tau-containing astrocytes and in oligodendrocytes with coiled bodies. These findings show, for the first time, activation of precise kinases that regulate tau phosphorylation at specific sites in familial tauopathy.

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Association Between Globular Glial Tauopathies and Frontotemporal Dementia—Expanding the Spectrum of Gliocentric Disorders

2021

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IMPORTANCE Globular glial tauopathies (GGTs), as defined by a consensus study in 2013, belong to the group of frontotemporal lobar degenerations and expand the spectrum of glial-predominant neurodegenerative diseases. Three neuropathological subtypes of GGT (types I-III) are characterized by phosphorylated tau-immunopositive inclusions that are predominantly in oligodendroglia and/or astroglia in the frontal, temporal, and/or precentral cortices. Type II is largely restricted to the corticospinal system. The low incidence of GGT (<10% of cases of frontotemporal lobar degeneration with tau pathology), together with its unusual combination of neuronal and nonneuronal pathology, has hindered identification and accurate diagnosis. This review collated clinical, demographic, neuropathological, and genetic data from 88 published GGT cases identified on PubMed to examine the association between GGT and frontotemporal dementia and associated disorders.

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Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells

Cited by 88 publications

References 32 publications

Functional effects of tau gene mutations ΔN296 and N296H

Functional effects of tau gene mutations ΔN296 and N296H

Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation

Association Between Globular Glial Tauopathies and Frontotemporal Dementia—Expanding the Spectrum of Gliocentric Disorders

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