A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology

Kobayashi, Tomonori; Ota, Satoru; Tanaka, Kuniaki; Ito, Yuji; Hasegawa, Masato; Umeda, Yumi; Motoi, Yumiko; Takanashi, Masashi; Yasuhara, Masahiro; Anno, Midori; Mizuno, Yoshikuni; Mori, Hideo

doi:10.1002/ana.10447

Cited by 72 publications

(43 citation statements)

References 17 publications

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“…Various types of astrocytic inclusions are generated in familial FTLD-tau linked to mutations in exons 1 and 10 and in introns following exons 9 and 10, the morphology of which largely depends on the MAPT mutation. Intracytoplasmic tau-immunoreactive inclusions in FTLD-tau are represented by tufted-like astrocytes, astrocytic plaques, ramified astrocytes, TSAs, astrocytes with globular inclusions and other types with no specific names [17,33,34,36,37,66,[77][78][79][80][81][82][83][84][85][86]. Tufted astrocytes and astrocytic plaques practically do not co-exist in PSP and CBD [57], but these lesions appear in combination in FTLD-tau [29] (Figure 4).…”

Section: Introductionmentioning

confidence: 99%

Astrogliopathy in Tauopathies

Ferrer

2018

Neuroglia

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Astrocytes are involved in many diseases of the central nervous system, not only as reactive cells to neuronal damage but also as primary actors in the pathological process. Astrogliopathy is a term used to designate the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Astrocytopathy is utilized to name non-reactive astrogliosis covering hypertrophy, atrophy and astroglial degeneration with loss of function in astrocytes and pathological remodeling, as well as senescent changes. Astrogliopathy and astrocytopathy are hallmarks of tauopathies-neurodegenerative diseases with abnormal hyper-phosphorylated tau aggregates in neurons and glial cells. The involvement of astrocytes covers different disease-specific types such as tufted astrocytes, astrocytic plaques, thorn-shaped astrocytes, granular/fuzzy astrocytes, ramified astrocytes and astrocytes with globular inclusions, as well as others which are unnamed but not uncommon in familial frontotemporal degeneration linked to mutations in the tau gene. Knowledge of molecular differences among tau-containing astrocytes is only beginning, and their distinct functional implications remain rather poorly understood. However, tau-containing astrocytes in certain conditions have deleterious effects on neuronal function and nervous system integrity. Moreover, recent studies have shown that tau-containing astrocytes obtained from human brain tauopathies have a capacity for abnormal tau seeding and spreading in wild type mice. Inclusive conceptions include a complex scenario involving neurons, glial cells and local environmental factors that potentiate each other and promote disease progression in tauopathies.

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Section: Introductionmentioning

confidence: 99%

Astrogliopathy in Tauopathies

Ferrer

2018

Neuroglia

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“…The study of FTDP-17 continues to throw light on some of these disorders, as exemplified by a clinical picture of progressive supranuclear palsy in cases with the R5L and ⌬N296 tau mutations and the recently identified L266V mutation. [7][8][9] Six tau isoforms are produced in the adult human brain by alternative mRNA splicing of exons 2, 3, and 10. 10 Three isoforms with three repeats (3R), and three isoforms with four repeats (4R), differing from each other by the presence of exon 10, are found in equal amounts in normal brain.…”

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confidence: 99%

Variable phenotypic expression and extensive tau pathology in two families with the novel tau mutation L315R

Herpen¹,

Rosso

Serverijnen³

et al. 2003

Annals of Neurology

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Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe two Dutch families with familial frontotemporal dementia associated with the novel missense mutation L315R in exon 11 of tau. The age at onset of disease showed a large variation within each family, ranging from 25 to 64 years. Incomplete penetrance was established in an 82-year-old mutation carrier with no signs of dementia and appeared probable in two additional subjects. The brains of two affected subjects were studied and showed extensive tau pathology in neurons (Pick-like inclusions) and astroglial cells, particularly in the frontotemporal cortex and the hippocampal formation. Sarkosyl-insoluble tau extracted from the cerebral cortex showed the presence of straight and twisted tau filaments and a pattern of pathological tau bands similar to that of Pick's disease. Upon dephosphorylation, only five of the six brain tau isoforms were observed, with the shortest isoform being undetectable. All six tau isoforms were present in soluble brain tau. Recombinant tau proteins with the L315R mutation showed a reduced ability to promote microtubule assembly.

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“…Both the R5H and R5L mutations in exon 1 of tau lead to neuronal and glial tau pathology, despite the fact that all 6 tau isoforms mutated. The L266V mutation affecting all 6 isoforms is associated with severe astrocytic tau pathology (resembling tufted astrocytes of PSP) [20], similar to that in the L315R mutation.…”

Section: Tau Mutations In Ftdp-17mentioning

confidence: 98%

“…Other new mutations continue to throw light on the phenotypic variation and the pathophysiological process in FTDP-17, as exemplified by the recently identified R5L, R5H, L266V and ¢N296 mutations in tau [17][18][19][20]. PSP was observed in a patient with the R5L mutation as well as in 2 siblings homozygous for the ¢N296 mutation [17,19], whereas the R5H mutation has been described in a patient with late-onset dementia [19].…”

Section: Tau Mutations In Ftdp-17mentioning

confidence: 99%

Phenotypic Variation in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17

Swieten

Rosso

Herpen³

et al. 2004

Dement Geriatr Cogn Disord

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Hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in the tau gene shows a wide range in age at onset, several distinct clinical presentations, and a spectrum of tau pathology. Although the clinical and pathological phenotype often correlate with the location of the mutation, there also exists considerable interfamilial and intrafamilial phenotypical variation. Not all families with FTDP-17 do have mutations and deposition of hyperphosphorylated tau in the brain, but show ubiquitin-positive, tau-negative inclusions. Future research should focus on the role of other genetic and environmental factors in this form of FTDP-17, whereas the responsible gene defect(s) has still to be identified for hereditary FTD without tau mutations.

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A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology

Cited by 72 publications

References 17 publications

Astrogliopathy in Tauopathies

Astrogliopathy in Tauopathies

Variable phenotypic expression and extensive tau pathology in two families with the novel tau mutation L315R

Phenotypic Variation in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17

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