Search

Abstract: Tau is the major protein exhibiting intracellular accumulation in Alzheimer disease. The mechanisms leading to its accumulation are not fully understood. It has been proposed that the proteasome is responsible for degrading tau but, since proteasomal inhibitors block both the ubiquitin-dependent 26S proteasome and the ubiqutin-independent 20S proteasome pathways, it is not clear which of these pathways is involved in tau degradation. Some involvement of the ubiquitin ligase, CHIP in tau degradation has also been postulated during stress. In the current studies, we utilized HT22 cells and tau-transfected E36 cells in order to test the relative importance or possible requirement of the ubiquitin-dependent 26S proteasomal system versus the ubiquitin-independent 20S proteasome, in tau degradation. By means of ATP-depletion, ubiquitinylation-deficient E36ts20 cells, a 19S proteasomal regulator subunit MSS1-siRNA approaches, and in vitro ubiquitinylation studies, we were able to demonstrate that ubiquitinylation is not required for normal tau degradation. [Copyright &y& Elsevier]

4-Hydroxynonenal (HNE) is a lipid peroxidation product that is able to modify proteins. HNE-modified proteins are degraded to a considerable extend by the proteasomal system. It is unclear whether the recognition of HNE-modified proteins is mediated by ubiquitin, or whether the ubiquitin-independent proteasomal pathway is involved. In this study we demonstrate that HNE-modified GAPDH is preferentially ubiquitinated in vitro. In an attempt to demonstrate the formation of poly-ubiquitinated HNE-modified proteins in living cells we explored E36 fibroblasts. A clear rise in HNE-protein modification could be demonstrated after HNE treatment of the cells. Using inhibitors, we could show that the ubiquitin-dependent, ubiquitin-independent, and the lysosomal pathways affect the presence of HNE-modified proteins. We conclude that, although several proteolytic pathways exist for the degradation of HNE-modified proteins, there is the possibility of involvement of ubiquitin-dependent degradation. [ABSTRACT FROM AUTHOR]