Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits

Exonic and intronic mutations in Tau cause familial neurodegenerative syndr omes characterized by frontotemporal dementia and dysfunction of multiple c ortical and subcortical circuits. Here we describe a G389R mutation in exon 13 of Tau. When 38 years old, the proband presented with progressive aphas ia and memory disturbance, followed by apathy, indifference, and hyperphagi a. Repeated magnetic resonance imaging showed the dramatic progression of c erebral atrophy. Positron emission tomography revealed marked glucose hypom etabolism that was most severe in left frontal, temporal, and parietal cort ical regions. Rigidity, pyramidal signs and profound dementia progressed un til death at 43 years of age. A paternal uncle, who had died at 43 years of age, had presented with similar symptoms. The proband's brain showed numer ous tau-immunoreactive Pick body-like inclusions in the neocortex and the f ascia dentata of the hippocampus. In addition, large numbers of tan-positiv e filamentous inclusions were present in axone in the frontal, temporal, an d parietal lobes. Immunoblot analysis of sarkosyl-insoluble tau showed 2 ma jor bands of 60 and 64 kDa. Upon dephosphorylation, these bands resolved in to 4 bands consisting of three- and four-repeat tau isoforms. Most isolated tau filaments were straight and resembled filaments found in Alzheimer dis ease and some frontotemporal dementias with tau mutations. A smaller number of twisted filaments was also observed. Biochemically, recombinant tau pro teins with the G389R mutation showed a reduced ability to promote microtubu le assembly, suggesting that this may be the primary effect of the mutation . Taken together, the present findings indicate that the G389R mutation in Tau can cause a dementing condition that closely resembles Pick's disease.