Altered conformation of recombinant frontotemporal dementia-17 mutant tau proteins Gregory A. Jicha a , Julia M. Rockwood a , Benjamin Berenfeld a , Mike Hutton b , Peter Davies a, * a Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forcheimer 526, Bronx, NY 10461, USA b Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA Received 3 November 1998; accepted 12 November 1998 Abstract 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 frontotem- poral 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 micro- tubule binding, microtubule polymerization, and the abnormal aggregation of tau seen in a variety of neurodegenerative diseases.  1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Frontotemporal dementia; Tau; Conformation Recently, a series of both non-coding (intronic) and cod- ing (exonic) mutations in the tau gene have been linked to a family of autosomal dominant dementias referred to as fron- totemporal dementia-17 [4,7,8]. This family of inherited diseases is characterized by extensive tau pathology, spon- giosis, and neuronal loss [8]. While these recent discoveries suggest that alterations in tau may play a central role in the pathogenesis of a variety of tau-related neurodegenerative diseases, it is unclear how mutations in the tau gene can lead to the degenerative cascade seen in frontotemporal demen- tia-17. While linkage analysis has demonstrated that these mutations segregate with the disease in affected families [4,7,8], it is unclear if they are causative in the disease process or are merely benign polymorphisms that segregate with causative mutations in an as yet undetermined neigh- boring gene. It has been proposed that the non-coding (intronic) mutations affect the alternative splicing of tau mRNA [4,7,8], favoring excess translation of the four repeat tau isoforms over the three repeat isoforms, it is unclear how this potential imbalance could lead to the neurodegeneration seen in affected individuals. While definitive answers to these questions await further analysis it should be noted that the coding mutations in the tau gene can be readily analyzed with existing methodologies, and such studies may help to elucidate the role tau plays in the neurodegen- erative cascade seen in frontotemporal dementia-17 patients. At present, four coding mutations linked to frontotem- poral dementia-17 have been reported. G272V, P301L, and V337M (numbering according to the amino acid sequence of the longest 441 amino acid tau isoform) muta- tions cluster in and near the microtubule binding repeats in the flexible hinge region characterized by a highly con- served PGGG motif [2]. As such it is possible that these mutations directly influence the tau-microtubule interaction leading to a neurodegenerative state. This hypothesis, how- ever, is weakened by the facts that (1) mice expressing no tau at all exhibit no obvious neuropathology [3] and (2) the autosomal dominant nature of frontotemporal dementia-17 in which patients carry a normal tau allele that could poten- tially overcome the limitation of an altered gene product [4,7,8]. Another mutation, R406W lies outside the micro- tubule binding domains and flanking regions and is unlikely Neuroscience Letters 260 (1999) 153–156 0304-3940/99/$ - see front matter  1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(98)00980-X * Corresponding author. Tel.: +1 718 4302053; fax: +1 718 4308541; e-mail: davies@aecom.yu.edu