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Degradation of Tau by Lysosomal Enzyme Cathepsin D: Implication for Alzheimer Neurofibrillary Degeneration
Author(s) -
Kenessey Agnes,
Nacharaju Parimala,
Ko Liwen,
Yen ShuHui
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69052026.x
Subject(s) - proteolysis , cathepsin d , chemistry , amino acid , biochemistry , cathepsin , extracellular , tau protein , microbiology and biotechnology , cleavage (geology) , enzyme , alzheimer's disease , biology , medicine , paleontology , disease , pathology , fracture (geology)
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 Phe 8 ‐Glu 9 , Met 419 ‐Val 420 , Thr 427 ‐Leu 428 ‐Ala 429 , and Leu 436 ‐Ala 437 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.