The role of tau (MAPT) in frontotemporal dementia and related tauopathies

Abstract

Tau is a multifunctional protein that was originally identified as a microtubule-associated protein. In patients diagnosed with frontotemporal dementia and parkinsonism linked to chromosome 17, mutations in the gene encoding tau (MAPT) have been identified that disrupt the normal binding of tau to tubulin resulting in pathological deposits of hyperphosphorylated tau. Abnormal filamentous tau deposits have been reported as a pathological characteristic in several other neurodegenerative diseases, including frontotemporal dementia, Pick Disease, Alzheimer disease, argyrophilic grain disease, progressive supranuclear palsy, and corticobasal degeneration. In the last five years, extensive research has identified 34 different pathogenic MAPT mutations in 101 families worldwide. In vitro, cell-free and transfected cell studies have provided valuable information on tau dysfunction and transgenic mice carrying human MAPT mutations are being generated to study the influence of MAPT mutations in vivo. This mutation update describes the considerable differences in clinical and pathological presentation of patients with MAPT mutations and summarizes the effect of the different mutations on tau functioning. In addition, the role of tau as a genetic susceptibility factor is discussed, together with the genetic evidence for additional causal genes for tau-positive as well as tau-negative dementia.

Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety

“…Different mutations in this gene can cause progressive supranuclear palsy or frontotemporal dementia with parkinsonism, as well as other disorders. 91 Exposure to stress may differentially impact the function of brain-body pathways involved in regulating syndromal depression and anxiety, depending on an individual's level of BDNF (according to the presence of Met or Val alleles). Of course, this possibility needs to be examined in clinical samples, to determine if these pathways predict depression and anxiety at the level of disorder.…”

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

“…Pathologically, frontal and/or temporal brain regions are degenerated. Based on the variable presence and composition of pathologic brain inclusions, FTLD can be subdivided in three pathologic subtypes: FTLD with tau-positive brain deposits (FTLD-tau) [Rademakers et al, 2004], FTLD with tau-negative ubiquitin-positive inclusions (FTLDU), and FTLD without inclusions (dementia lacking distinctive histopathology [DLDH]). Positive family history is observed in up to 50% of FTLD patients Rosso et al, 2003] and most families are linked with a region at chromosome 17q21.…”

“…In a number of these families, mutations were identified in the microtubule-associated protein tau gene (MAPT; MIM] 157140) [Hutton et al, 1998;Poorkaj et al, 1998]. MAPT mutations were strictly associated with FTLD-tau pathology [Rademakers et al, 2004]. Despite extensive mutation analyses of MAPT, chromosome 17q21-linked FTLD families with FTLDU pathology (FTLDU-17; MIM] 607485) did not segregate a MAPT mutation.…”

Slow vertical saccades in the frontotemporal dementia with motor neuron disease

“…Finally, genetic studies have revealed that pathologically confirmed cases of PSP, CBD, and FTLD share mutations from a single gene (MAPT) [6,10,21,29,30,36]. Therefore, to encompass the whole spectrum of these disorders, an umbrella term called "Pick complex" has been proposed [17,20,26].…”