Degradation of tau by lysosomal enzyme cathepsin D: implication for Alzheimer neurofibrillary degeneration.
The degradation of different isoforms of human recombinant tau (R-tau; T39, T40, and T44) and fetal tau (F-tau) by cathepsin D ( CD) was investigated. Gel electrophoresis and Coomassie Blue staining of different R-tau species digested at pH 3.5 showed very little differences in CD susceptibility. Immunoblotting analyses revealed that amino and carboxy termini of tau were cleaved before other regions. F-tau was most vulnerable to proteolysis at both termini. Digestion of R-tau with 0.01 unit of CD/ml at pH 3.5 resulted in cleavage between Phe8-Glu9, Met419-Val420, Thr427-Leu428-Ala429, and Leu436-Ala437 as determined by amino acid sequencing and mass spectroscopy (numbering of amino acids was based on T40). With higher concentrations of CD (1 unit/ml), additional sites of digestion were detected between amino acids 34-161, 200-257, and 267-358. The cleavage sites at amino acids 34-161 and 267-358 were observed at pH 3.5, whereas that at amino acids 200-257 was detected at pH 7. 0. Our results suggest that CD cleavage of tau could generate tau fragments with intact microtubule binding domains, which could have a role in the pathogenesis of paired helical filaments (PHFs) in Alzheimer's disease. Such proteolysis might also contribute to the changes of PHF phenotype observed in intracellular and extracellular tangles.[1]References
- Degradation of tau by lysosomal enzyme cathepsin D: implication for Alzheimer neurofibrillary degeneration. Kenessey, A., Nacharaju, P., Ko, L.W., Yen, S.H. J. Neurochem. (1997) [Pubmed]
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