Limits...
The ubiquitin-proteasome system in Alzheimer's disease.

Oddo S - J. Cell. Mol. Med. (2008)

Bottom Line: Evidence has suggested that protein accumulation may result from a dysfunction in the ubiquitin proteasome system (UPS).Indeed, there is clear genetic and biochemical evidence of an involvement of the ubiquitin proteasome system in AD.This review summarizes the data supporting an involvement of the UPS in the pathogenesis of AD, focusing on the data showing the relationship between Abeta and tau, the two hallmark lesions of AD, and the UPS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology and Behavior University of California, Irvine, CA 92697-4545, USA. soddo@uci.edu

ABSTRACT
Accumulation of proteins is a recurring event in many neurodegenerative diseases, including Alzheimer's disease (AD). Evidence has suggested that protein accumulation may result from a dysfunction in the ubiquitin proteasome system (UPS). Indeed, there is clear genetic and biochemical evidence of an involvement of the ubiquitin proteasome system in AD. This review summarizes the data supporting an involvement of the UPS in the pathogenesis of AD, focusing on the data showing the relationship between Abeta and tau, the two hallmark lesions of AD, and the UPS.

Show MeSH

Related in: MedlinePlus

Schematic representation of a possible scenario by which Aβ can mediate tau accumulation via the pro-teasome. During normal conditions, ubiquitinated tau is targeted to the proteasome for turnover (A). Aβ deposit can inhibit the proteasome impairing its normal function. As a consequence, tau cannot be degraded by the pro-teasome and accumulates into NFT (B).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3822529&req=5

fig02: Schematic representation of a possible scenario by which Aβ can mediate tau accumulation via the pro-teasome. During normal conditions, ubiquitinated tau is targeted to the proteasome for turnover (A). Aβ deposit can inhibit the proteasome impairing its normal function. As a consequence, tau cannot be degraded by the pro-teasome and accumulates into NFT (B).

Mentions: Further supporting a role for the proteasome in the Aβ and tau interaction is the data showing an impairment of proteasome activity in the 3×Tg-AD mice that correlates with an increase in Aβ oligomers [82]. Remarkably, accumulation of Aβ and tau was found after direct inhibition of proteasome activity in the 3×Tg-AD mice [82]. Taken together, these data strongly suggest that the proteasome is a molecular link between Aβ and tau pathology (Fig. 2). Further studies will need to elucidate how Aβ-dependent pro-teasome inhibition can lead to tau accumulation. Considering the clear role of CHIP in tau removal, it is tempting to speculate that Aβ accumulation may alter CHIP function thus leading to the accumulation of tau.


The ubiquitin-proteasome system in Alzheimer's disease.

Oddo S - J. Cell. Mol. Med. (2008)

Schematic representation of a possible scenario by which Aβ can mediate tau accumulation via the pro-teasome. During normal conditions, ubiquitinated tau is targeted to the proteasome for turnover (A). Aβ deposit can inhibit the proteasome impairing its normal function. As a consequence, tau cannot be degraded by the pro-teasome and accumulates into NFT (B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822529&req=5

fig02: Schematic representation of a possible scenario by which Aβ can mediate tau accumulation via the pro-teasome. During normal conditions, ubiquitinated tau is targeted to the proteasome for turnover (A). Aβ deposit can inhibit the proteasome impairing its normal function. As a consequence, tau cannot be degraded by the pro-teasome and accumulates into NFT (B).
Mentions: Further supporting a role for the proteasome in the Aβ and tau interaction is the data showing an impairment of proteasome activity in the 3×Tg-AD mice that correlates with an increase in Aβ oligomers [82]. Remarkably, accumulation of Aβ and tau was found after direct inhibition of proteasome activity in the 3×Tg-AD mice [82]. Taken together, these data strongly suggest that the proteasome is a molecular link between Aβ and tau pathology (Fig. 2). Further studies will need to elucidate how Aβ-dependent pro-teasome inhibition can lead to tau accumulation. Considering the clear role of CHIP in tau removal, it is tempting to speculate that Aβ accumulation may alter CHIP function thus leading to the accumulation of tau.

Bottom Line: Evidence has suggested that protein accumulation may result from a dysfunction in the ubiquitin proteasome system (UPS).Indeed, there is clear genetic and biochemical evidence of an involvement of the ubiquitin proteasome system in AD.This review summarizes the data supporting an involvement of the UPS in the pathogenesis of AD, focusing on the data showing the relationship between Abeta and tau, the two hallmark lesions of AD, and the UPS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology and Behavior University of California, Irvine, CA 92697-4545, USA. soddo@uci.edu

ABSTRACT
Accumulation of proteins is a recurring event in many neurodegenerative diseases, including Alzheimer's disease (AD). Evidence has suggested that protein accumulation may result from a dysfunction in the ubiquitin proteasome system (UPS). Indeed, there is clear genetic and biochemical evidence of an involvement of the ubiquitin proteasome system in AD. This review summarizes the data supporting an involvement of the UPS in the pathogenesis of AD, focusing on the data showing the relationship between Abeta and tau, the two hallmark lesions of AD, and the UPS.

Show MeSH
Related in: MedlinePlus