Frontotemporal Dementia with Tau Pathology

Abstract

Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. Filamentous deposits made of tau constitute a major defining characteristic of several neurodegenerative diseases known as tauopathies including Alzheimer’s disease. The involvement of tau in neurodegeneration has been clarified by the identification of genetic mutations in the tau gene in cases with familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Although the mechanism through which tau mutations lead to neuronal death is still unresolved, it is clear that tau mutations lead to formation of tau filaments that have a different morphology, contain different types of tau isoforms and produce distinct tau deposits. The range of tau pathology identified in FTDP-17 recapitulates the tau pathology present in sporadic tauopathies and indicates that tau dysfunction plays a major role also in these diseases.

Axonal Stress Kinase Activation and Tau Misbehavior Induced by Kinesin-1 Transport Defects

“…Axonal transport defects have been suggested as the ultimate cellular mechanism impaired by tau protein loss of function and tau toxic gain of function both in sporadic and familial tauopathies (Ballatore et al, 2007;Gasparini et al, 2007). However, the initial events leading to tau misbehavior remain unknown.…”

From Protein Tangles to Genetic Variants: The Central Role of Tau in Neurodegenerative Disease

“…Mutations in coding regions outside of exon 10 present neuronal tau pathology with glial cells unaffected. The tau inclusions are formed by filaments that are composed of both 3R and 4R isoforms and that resemble the PHFs and SFs found in Alzheimer's disease or show twisted ribbon morphology (Gasparini et al, 2007;Goedert, 2005). However, the mutation K257T in exon 9 leads to the deposition of tangles predominantly composed of 3R tau species (Rizzini et al, 2000).…”

“…FTD is one of the most common forms of dementia besides Alzheimer's disease. While the majority of cases are thought to occur sporadically, familial cases of the disease were described as far back as 1939 (Gasparini et al, 2007). In 1994, a familial case of dementia with parkinsonism was described.…”

“…The only known mutations outside the microtubule-binding domain have been found in exons 1 (R5H and R5L) and 13 (G389R, R406W and T427M). While most mutations in these exons as well as exons 9, 11 and 12 affect all tau isoforms, only 4R tau is affected by mutations in exon 10 (Gasparini et al, 2007). The primary mechanism by which missense and deletion mutations in the coding regions alter the properties of tau protein is by decreasing affinity for microtubules.…”

“…The regulation of exon 10 splicing through intronic sequences is explained by two alternative models: The stem-loop theory proposes that a secondary stem loop structure blocks binding of U1 snRNP to the 5' splice site. The intronic mutations +10, +11, +12, +13, +14 and +16 disrupt the stem loop in this model, thereby increasing exon 10 splicing (Gasparini et al, 2007;Hutton et al, 1998;Spillantini et al, 1998). The alternative linear sequence theory suggests that three sequences in the intron following exon 10 modulate splicing: an intron splicing silencer and an intron splicing modulator, which are located downstream of the 5' splicing site.…”