Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17.
Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17.
Tau proteins aggregate as cytoplasmic inclusions in a number of neurodegenerative diseases, including Alzheimer's disease and hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
Pathological tau proteins that constitute the basic matrix of neuronal inclusions observed in numerous neurodegenerative disorders are disease specific.
These data suggest that the previously identified mutations in the tau gene seen in frontotemporal dementia-17 are not merely benign polymorphisms, but may have functional consequences for microtubule binding, microtubule polymerization, and the abnormal aggregation of tau seen in a variety of neurodegenerative diseases.
Evidence from familial fronto-temporal dementia with parkinsonism linked to chromosome 17 suggests that tau protein deposition is a primary pathogenic event in some neurodegenerative diseases.
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.
Filamentous tau protein deposits are also the defining characteristic of other neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy, and corticobasal degeneration.
Filamentous tau protein deposits are also the defining characteristic of other neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration.
The discovery of multiple tau gene mutations that are pathogenic for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 in many kindreds, as well as the demonstration that tau polymorphisms are genetic risk factors for sporadic tauopathies, directly implicate tau abnormalities in the onset/progression of neurodegenerative disease.
The mechanism by which this common variability in the tau gene influences the development of these neurodegenerative diseases is unclear; however, it further suggests a central role for tau in the pathogenesis of several neurodegenerative conditions including Alzheimer's disease (AD).
Intracellular filamentous inclusions made of either the microtubule-associated protein tau or the protein alpha-synuclein define the majority of cases of neurodegenerative disease.
Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that is associated with mutations in the tau gene and with the pathological accumulation of hyperphosphorylated tau protein in affected brain cells in about a quarter of cases.
Intraneuronal aggregates of hyperphosphorylated tau proteins, referred to as pathological tau, are found in brain areas of demented patients affected by numerous different neurodegenerative disorders.
These results imply that NFs are pathological chaperones in the development of tau spheroids and suggest a role for NFs in the pathogenesis of neurofibrillary tau lesions in neurodegenerative disorders that contain both NFs and tau proteins.
Because multiple tau gene mutations are pathogenic for FTDP-17 and tau polymorphisms appear to be genetic risk factors for sporadic progressive supranuclear palsy and corticobasal degeneration, tau abnormalities are linked directly to the etiology and pathogenesis of neurodegenerative disease.
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.
The specific mutation on the tau gene responsible for a neurodegenerative disease known as pallido-ponto-nigral degeneration (PPND) was recently located.
Progressive supranuclear palsy (PSP) is a tau deposition neurodegenerative disorder which usually occurs in sporadic form and is associated with a common variant of the tau gene.