New insights into genetic and molecular mechanisms of brain degeneration in tauopathies

Abundant neurofibrillary lesions consisting of the microtubule associated p rotein tau and amyloid beta peptide deposits are the defining lesions of Al zheimer's disease. Prominent filamentous tau pathology and brain degenerati on in the absence of extracellular amyloid deposition characterize a number of other neurodegenerative disorders (i.e. progressive supranuclear palsy. corticobasal degeneration. Picks disease) collectively referred to as tauo pathies. The discovery of multiple tau gene mutations that are pathogenic f or hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 in many kindreds, as well as the demonstration that tau polymorphisms a re genetic risk factors for sporadic tauopathies, directly implicate tau ab normalities in the onset/progression of neurodegenerative disease. Differen t tau gene mutations may be pathogenic by impairing the functions of tau or by perturbing the splicing of the tau gene, thereby resulting in biochemic ally and structurally distinct tau aggregates. However, since specific poly morphisms and mutations in the tan gene lead to diverse phenotypes. it is p lausible that additional genetic or epigenetic factors influence the clinic al and pathological manifestations of both familial and sporadic tauopathie s. Thus, efforts to develop animal models of tan-mediated neurodegeneration should provide further insights into the onset and progression of tauopath ies as well as Alzheimer's disease, and they could accelerate research to d iscover more effective therapies for these disorders. (C) 2000 Elsevier Sci ence B.V. All rights reserved.