Distinct Tau Gene Mutations Induce Specific Dysfunctions/Toxic Properties in Tau Proteins Associated With Specific FTDP-17 Phenotypes

Abstract

Abundant neurofibrillary tangles (NFTs) composed predominantly of aggregated paired helical filaments (PHFs) formed by abnormally phosphorylated tau proteins known as PHFtau comprise one of the two signature brain lesions required for a definite diagnosis of Alzheimer’s disease (AD), but several other hereditary and sporadic neurodegenerative disorders are characterized by abundant accumulations of filamentous tau inclusions in specific populations of neurons with or without similar glial cell inclusions. Despite phenotypic and genotypic heterogeneity, central nervous system (CNS) diseases with prominent tau-rich filamentous inclusions are collectively known as tauopathies. While some tauopathies (e.g., AD) are associated with other diagnostic lesions (e.g., amyloid plaques), the accumulation of filamentous tau inclusions is the predominant or only diagnostic neuropathological feature of several neurodegenerative tauopathies, although these inclusions are accompanied by neuron loss and gliosis. Here we review evidence based on the discovery of pathogenic tau gene mutations in fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and a growing body of other data indicating that the progressive accumulation of intracellular filamentous tau inclusions alone is sufficient to induce the onset and/or progression of neurodegenerative disease, due to the dysfunction and death of affected neurons and glial cells in selectively vulnerable regions of the CNS.