Thus, splicing of tau might critically influence the physiological functions of tau protein as well as the pathogenesis of neurodegenerative diseases with tauopathy.
Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.
Since FTDP-17tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies.
Hereditary frontotemporal dementia and parkinsonism (FTDP) linked to chromosome 17 (FTDP-17) constitutes a new form of tauopathy, and mutations in the tau gene have recently been reported in some affected families.
The intracellular accumulation of tau protein and its aggregation into filamentous deposits is the intracellular hallmark of neurofibrillary degenerative diseases such as Alzheimer's Disease and familial tauopathies in which tau is now thought to play a critical pathogenic role.
In addition to the tau mutations, a common extended haplotype in the tau gene also appears to be a risk factor in the development of the apparently sporadic tauopathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).
However, since specific polymorphisms and mutations in the tau gene lead to diverse phenotypes, it is plausible that additional genetic or epigenetic factors influence the clinical and pathological manifestations of both familial and sporadic tauopathies.
Although transgenic mice expressing wild-type human tau or variants thereof with an FTDP-17 mutation result in tau pathologies and brain degeneration similar to that seen in human tauopathies, the precise mechanisms leading to the onset and progression of neurodegenerative disorders remain incompletely understood.
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a familial neurological disorder, characterized genetically by autosomal dominant inheritance, clinically by behavioral abnormalities and parkinsonism, and neuropathologically by tauopathy.
The finding that specific tau gene mutations lead to diverse FTDP-17 phenotypes raises the possibility that the clinical and pathological expression of hereditary and related sporadic tauopathies may be influenced by tau gene polymorphisms, other genetic factors and epigenetic events.
Familial tauopathies linked to tau gene mutations showing clinical and neuropathological overlap with sporadic progressive supranuclear palsy have been described.
The R406W tau mutation found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) causes a hereditary tauopathy clinically resembling Alzheimer's disease.
Mutations of the tau gene in frontotemporal dementia with parkinsonism and genetic association of the tau locus with progressive supranuclear palsy and corticobasal degeneration directly implicate the tau gene in the aetiology of these tauopathies.