Mutations in the gene for the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In this study we compared the presence of the P301L mutated tau protein from brain material of patients with that of the normal 4-repeat, using polyclonal antibodies specific for the P301L point mutation and its normal counterpart. We determined the relative ratio of mutated versus normal tau protein in the sarkosyl-soluble and -insoluble protein fractions from several brain regions. Although mutated and normal tau proteins are both present in the sarkosyl-insoluble deposits, quantitative analysis showed that the mutated protein is the major component. In the sarkosyl-soluble fraction of frontal and temporal cortex the overall ratio of 3-repeat versus 4-repeat tau isoforms is unchanged but there is a dramatic depletion of mutant tau protein. Furthermore, we observed an increase in tau-immunoreactive cleavage products with the P301L antibody, suggesting that the mutant protein is partly resistant to degradation and this is confirmed by pulse-chase experiments. This is the first direct evidence using patient material that shows a selective aggregation of mutant tau protein resulting in sarkosyl-insoluble deposits and the specific depletion of mutated tau protein in the soluble fraction.

Aged, Amino Acid Substitution, Animals, Antibodies, COS Cells, Cerebral Cortex/*metabolism, Chromosomes, Human, Pair 17, Dementia/*genetics/metabolism, Humans, Immunohistochemistry, Microtubule-Associated Proteins/*genetics/immunology, Middle aged, PC12 Cells, Parkinsonian Disorders/*genetics/metabolism, Point Mutation, Prefrontal Cortex/metabolism, Rabbits, Rats, Research Support, Non-U.S. Gov't, tau Proteins/*genetics/immunology
Human Molecular Genetics
Erasmus MC: University Medical Center Rotterdam

Rizzu, P, Joosse, M, Ravid, R, Kamphorst, W, van Swieten, J.C, Willemsen, R, … Heutink, P. (2000). Mutation-dependent aggregation of tau protein and its selective depletion from the soluble fraction in brain of P301L FTDP-17 patients. Human Molecular Genetics. Retrieved from