Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17

Ghetti, Bernardino; Wszołek, Zbigniew K.; Boeve, Bradley F.; Spina, Salvatore; Goedert, Michel

doi:10.1002/9781444341256.ch14

Cited by 48 publications

(45 citation statements)

References 140 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Astrocytes bearing abnormal tau are similar to non-specific reactive astrocytes showing partial disruption of the astroglial cytoskeleton and unique accumulation of abnormal tau in astrocyte foot processes, thus resulting in marked perivascular tau deposition. Variegated astroglial, and neuronal and oligodendroglial inclusions, are found in frontotemporal lobar degeneration linked to mutations in MAPT (11), but in no case does tau deposition in astrocytes have a profile like that seen in the present astrocyte-predominant familial tauopathy.…”

Section: Discussionmentioning

confidence: 86%

Familial Behavioral Variant Frontotemporal Dementia Associated With Astrocyte-Predominant Tauopathy

Ferrer

Legati

García-Moncó

et al. 2015

J Neuropathol Exp Neurol

View full text Add to dashboard Cite

A familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy is described in 2 sisters born from consanguineous parents. The neuropathological examination revealed massive accumulation of abnormally hyper-phosphorylated, conformational, truncated at aspartic acid 421, ubiquitinated, and nitrated tau at Tyr29 in cortical astrocyte (including their perivascular foot processes) and Bergmann glia. Smaller amounts of abnormal tau were observed in neurons and rarely in oligodendrocytes. There was decreased expression of glial glutamate transporter in the majority of tau-positive astrocytes. Gel electrophoresis of sarkosyl-insoluble fractions showed 2 bands of 64 and 60 kDa and a doublet of 67–70 kDa (which are different from those seen in Alzheimer disease and in typical 4R and 3R tauopathies) together with several bands of lower molecular weight indicative of truncated tau. Analysis of expression of MAPT isoforms further revealed altered splicing and representation of tau isoforms involving exons 2, 3 and 10. Genetic testing revealed no known mutations in PSEN1, PSEN2, APP, MAPT, GRN, FUS, and TARDBP, and no pathological expansion in C9ORF72. However, a novel rare heterozygous sequence variant (p.Q140H) of uncertain significance was identified in FUS in both siblings.

show abstract

Section: Discussionmentioning

confidence: 86%

Familial Behavioral Variant Frontotemporal Dementia Associated With Astrocyte-Predominant Tauopathy

Ferrer

Legati

García-Moncó

et al. 2015

J Neuropathol Exp Neurol

View full text Add to dashboard Cite

show abstract

“…All these astrocytic inclusions in sporadic tauopathies are composed of 4Rtau isoforms, but certain astrocytes in PiD and PSP contain 3Rtau [37]. Astrocytic inclusions in FTLD-tau depend on the mutation, but they are largely composed of 4Rtau [33,37,66].…”

Section: Post-translational Tau Modifications and Tau Kinases In Tau-mentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract

“…Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 In the 1980s and 1990s, dominantly inherited forms of FTD were identified (Ghetti et al 2011). Extrapyramidal signs resembling CBS and PSP also featured prominently.…”

Section: Frontotemporal Dementia and Progressive Supranuclear Palsy (mentioning

confidence: 99%