Altered conformation of recombinant frontotemporal dementia-17 mutant tau proteins

Recently, a series of both non-coding (intronic) and coding (exonic) mutations in the tau gene have been linked to a family of autosomal dominant dementias referred to as frontotemporal dementia-17. While linkage analysis has demonstrated that these mutations segregate with disease in affected families, it is unclear how mutant tau proteins could lead to the degenerative cascade seen in frontotemporal dementia-17. The present study demonstrates that coding mutations of tau seen in frontotemporal dementia-17 exhibit altered physical and structural characteristics as determined by reverse phase high performance liquid chromatography and circular dichroism spectroscopy. 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.