Tau is not normally degraded by the proteasome

Abstract

Tau-positive inclusions in neurons are consistent neuropathologic features of the most common causes of dementias such Alzheimer's disease and frontotemporal dementia. Ubiquitinated tau-positive inclusions have been reported in brains of Alzheimer's disease patients, but involvement of the ubiquitin-dependent proteasomal system in tau degradation remains controversial. Before considering the tau degradation in pathologic conditions, it is important to determine whether or not endogenous tau is normally degraded by the proteasome pathway. We therefore investigated this question using two complementary approaches in vitro and in vivo. Firstly, SH-SY5Y human neuroblastoma cells were treated with different proteasome inhibitors, MG132, lactacystin, and epoxomicin. Under these conditions, neither total nor phosphorylated endogenous tau protein levels were increased. Instead, an unexpected decrease of tau protein was observed. Secondly, we took advantage of a temperature-sensitive mutant allele of the 20S proteasome in Drosophila. Genetic inactivation of the proteasome also resulted in a decrease of tau levels in Drosophila. These results obtained in vitro and in vivo demonstrate that endogenous tau is not normally degraded by the proteasome.

Suppression of Autophagy and Activation of Glycogen Synthase Kinase 3beta Facilitate the Aggregate Formation of Tau

“…It has been reported that tau is not normally degraded by the proteasome given the fact that tau degradation by proteasome requires polyubiqutination of tau but it is difficult to observe polyubiqutinated tau in cells [23]. It has been suggested that autophagy might play a key role in the degradation of protein aggregates in age-related neurodegenerative diseases [24].…”

Tubulin-Mediated Binding of Human Immunodeficiency Virus-1 Tat to the Cytoskeleton Causes Proteasomal-Dependent Degradation of Microtubule-Associated Protein 2 and Neuronal Damage

“…Previous reports indicate that the expression of MAP proteins can be regulated by activation of calpain proteolytic pathway (Buddle et al, 2003) and, to a lesser extent, by the proteasomal pathway (David et al, 2002;Feuillette et al, 2005). Therefore, to investigate possible mechanisms involved in Tatmediated MAP2 breakdown, we treated Tat-expressing neurons with specific inhibitors of the calpain or proteasome pathways.…”

Aβ inhibits the proteasome and enhances amyloid and tau accumulation

“…Tau is generally thought to be a target for proteasome degradation but some recent data challenge this assertion (Cardozo and Michaud, 2002;David et al, 2002;Feuillette et al, 2005;Petrucelli et al, 2004). One report suggests that application of the protein synthesis blocker, cyclohexamide, increases tau levels, which are then further augmented by the application of a proteasome inhibitor, whereas application of the proteasome inhibitor alone actually resulted in a decrease in tau levels (Feuillette et al, 2005).…”

“…One report suggests that application of the protein synthesis blocker, cyclohexamide, increases tau levels, which are then further augmented by the application of a proteasome inhibitor, whereas application of the proteasome inhibitor alone actually resulted in a decrease in tau levels (Feuillette et al, 2005). We examined the effects of proteasome inhibition on tau degradation by transiently transfecting HEK cells with wildtype human tau (2N/4R) and treating a subset of these cells with 10 μM epoxomicin for 12 h, as previous work indicated that the half-life of tau in cells is about 12-14 h (David et al, 2002).…”