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F3‐02‐03: Tau truncation: The most productive post‐translational modification
Author(s) -
Novak Michal,
Zilka Norbert,
Kovacech Branislav,
Barath Peter,
Kontsekova Eva
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.1128
Subject(s) - tau protein , transgene , genetically modified mouse , truncation (statistics) , immunoprecipitation , microbiology and biotechnology , chemistry , biology , alzheimer's disease , biochemistry , antibody , genetics , disease , medicine , pathology , gene , statistics , mathematics
Background: Pathological truncations of human brain proteins represent the common feature of many neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, FTLD and polyglutamine disorders. It has been showed that protein truncations significantly change the structure and function of the proteins and thus can engender their pathological metamorphosis. We have shown that truncated forms of tau protein are comprised in the core of the paired helical filaments that represent the main constituent of neurofibrillary pathology in Alzheimer’s disease. Methods: In order to yield different truncated tau species with intact N-terminus, intact C-terminus and with double truncation we have used tandem immunoaffinity purification using monoclonal antibodies DC31N (aa 1-30), DC39C (aa 434-441) and DC190 (aa 368376) coupled to CNBr Sepharose (GE Healthcare). LC MALDI TOF/ TOF (Ultraflextreme from Bruker) was used to identify the truncation points of the tau proteins. Results:We have identified various truncated tau species of different molecular signature displaying distinct levels of phosphorylation and ubiquitination. These post-translational modifications cause significant and systematic shift in the electrophoretic mobility of truncated tau species resulting in groups of protein bands on SDS gels. This implicates that N-terminal truncation of tau protein in human AD brain is not a random process. To characterize the pathophysiology of AD specific truncated tau species, we have used transgenic rat model for AD expressing human truncated tau. Expression of the transgenic truncated tau protein induces formation of multiple novel truncated tau species that originate from both transgenic human tau and endogenous rat tau proteins. Conclusions: We show that tau truncation is the most productive post-translational modification in Alzheimer’s disease. Truncation of tau is not produced by random process, but by highly specific proteolytic cleavage and non-enzymatic fragmentation. Using transgenic rat model for AD, we have found that truncated tau generates novel truncated tau species derived from transgenic human tau and rat endogenous tau. These findings further corroborate the idea that appearance of truncated tau species starts self-perpetuating cycle of further tau protein truncation leading to and accelerating tau misfolding and formation of neurofibrillary pathology.