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Human Molecular Genetics, 2000, Vol. 9, No. 20 3075-3082
© 2000 Oxford University Press

Mutation-dependent aggregation of tau protein and its selective depletion from the soluble fraction in brain of P301L FTDP-17 patients

Patrizia Rizzu1,2, Marijke Joosse1, Rivka Ravid3, Andre Hoogeveen1, Wouter Kamphorst4, John C. van Swieten2, Rob Willemsen1 and Peter Heutink1,+

1Department of Clinical Genetics and 2Department of Neurology, Erasmus University, PO Box 1738, 3000 DR Rotterdam, The Netherlands, 3The Netherlands Brain Bank, 1105 AZ Amsterdam, The Netherlands and 4Department of Pathology, Vrije University 1081 HV Amsterdam, The Netherlands

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.

+ To whom correspondence should be addressed. Tel: +31 10 408 8136; Fax: +31 10 408 9489; Email: heutink@kgen.fgg.eur.nl


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