Tau protein degradation is catalyzed by the ATP/ubiquitin-independent 20S proteasome under normal cell conditions

Grune, Tilman; Botzen, Diana; Engels, Martina; Voss, Peter; Kaiser, Barbara; Jung, Tobias; Grimm, Stefanie; Ermak, Gennady; Davies, Kelvin J.A.

doi:10.1016/j.abb.2010.05.008

Cited by 75 publications

(70 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previously we reported that FKBP51 coordinated with Hsp90 to promote the accumulation of nonubiquitinated tau in the presence of a proteasome inhibitor (17). This suggested that FKBP51 may be playing a role in ubiquitin-independent tau degradation via the 20S proteasome, a process shown to be a major route of tau clearance (32,33). The 20S proteasome serves as the catalytic core for the 26S proteasome (34), and 20S proteasomes can be about 3-to 4-times more abundant in cells than 26S proteasomes (35).…”

Section: Fkbp51 Depletion Reduces Tau Levels In Brainmentioning

confidence: 99%

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

et al. 2013

View full text Add to dashboard Cite

Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5 -/-mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer's disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

show abstract

Section: Fkbp51 Depletion Reduces Tau Levels In Brainmentioning

confidence: 99%

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Tau turnover is catalyzed by the 20S proteasome (54). However, in AD, tau undergoes hyperphosphorylation, which reduces the proteasomal susceptibility of the protein (131).…”

Section: Protein Oxidation In Ndsmentioning

confidence: 99%

Protein Oxidation in Aging: Does It Play a Role in Aging Progression?

Reeg

Grune

2015

Antioxidants & Redox Signaling

Self Cite

170

134

View full text Add to dashboard Cite

Significance: A constant accumulation of oxidized proteins takes place during aging. Oxidation of proteins leads to a partial unfolding and, therefore, to aggregation. Protein aggregates impair the activity of cellular proteolytic systems (proteasomes, lysosomes), resulting in further accumulation of oxidized proteins. In addition, the accumulation of highly crosslinked protein aggregates leads to further oxidant formation, damage to macromolecules, and, finally, to apoptotic cell death. Furthermore, protein oxidation seems to play a role in the development of various age-related diseases, for example, neurodegenerative diseases. Recent Advances: The highly oxidized lipofuscin accumulates during aging. Lipofuscin formation might cause impaired lysosomal and proteasomal degradation, metal ion accumulation, increased reactive oxygen species formation, and apoptosis. Critical Issues: It is still unclear to which extent protein oxidation is involved in the progression of aging and in the development of some age-related diseases. Future Directions: An extensive knowledge of the effects of protein oxidation on the aging process and its contribution to the development of age-related diseases could enable further strategies to reduce age-related impairments. Strategies aimed at lowering aggregate formation might be a straightforward intervention to reduce age-related malfunctions of organs. Antioxid. Redox Signal. 23, 239-255.

show abstract

“…The proteasome may play a key role in delaying the accumulation of neurotoxic tau. In vitro, tau protein can be degraded by the 20S proteasome in an ATP/ubiquitin-independent manner 92 . However, other studies showed that tau proteasomal degradation is at least partially ubiquitin-dependent in cells 39 .…”

Section: Loss Of Clearance Mechanisms As a Determinant Of Ageingmentioning

confidence: 99%