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.
These findings suggest that tau proteins are not always assembled in abnormal filaments such as twisted ribbons, paired helical filaments and straight tubules in neurons and glial cells, which have been shown in previous cases with frontotemporal dementia and parkinsonism linked to chromosome 17.
These mice contain a tau gene with a mutation of the frontotemporal dementia parkinsonism (FTDP-17) type, in which valine is substituted with methionine residue 337.
In addition, disease-causing mutations in the tau gene on chromosome 17 have been detected in some families with autosomal dominant FTD and parkinsonism.
Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17.
However, since 1998, the identification of more than 25 mutations in the tau gene, associated with frontotemporal dementia and parkinsonism linked to chromosome 17, has demonstrated that tau dysfunction can lead to neurodegeneration and the development of clinical symptoms.
Autonomic function was investigated in five affected and five at-risk members of a single kinship of pallidopontonigral degeneration (PPND), which is a progressive syndrome of parkinsonism and frontotemporal dementia resulting from a mutation in the N279Ktau gene on chromosome 17.
Autonomic function was investigated in five affected and five at-risk members of a single kinship of pallidopontonigral degeneration (PPND), which is a progressive syndrome of parkinsonism and frontotemporal dementia resulting from a mutation in the N279K tau gene on chromosome 17.
The recent discovery of tau gene mutations in FTD with Parkinsonism linked to chromosome 17 has reinforced the direct role attributed to abnormal tau proteins (hyperphosphorylation) and thus raised the possibility to target specifically these processes by drugs (aetiopathogenic compounds).
The second part will deal with the recent discovery of tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 which demonstrates that tau dysfunction can lead to neurodegeneration.
Several distinct clinical syndromes presenting with parkinsonism have been associated with subcortical neurofibrillary degeneration and the abnormal accumulation of hyperphosphorylated tau protein in the brain.
The role 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.
The analysis of tau gene and the study of familial cases of tauopathies have led to the discovery of tau gene mutations that cause inherited dementia designated as Frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17).
Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one of the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau).
Because tau gene mutations are pathogenic for the autosomal dominant tauopathy "frontotemporal dementia and parkinsonism linked to chromosome 17," tau abnormalities are implicated directly in the onset and/or progression of disease.
Mutations in MAPT were previously identified in familial FTD with parkinsonism (FTDP-17); however, in FTDU-17 patients, no pathogenic mutations were found in exonic regions consistent with the lack of tauopathy in FTDU-17 brains.