The aggravating role of the ubiquitin–proteasome system in neurodegeneration

Abstract

Association of protein inclusions or aggregates within brain tissues of patients with neurodegenerative disorders has been widely reported. These inclusions are commonly characterised both by the presence of ubiquitylated proteins and the sequestration of components of the ubiquitin-proteasome system (UPS). Such observations have led to the proposition that the UPS has a direct role in their formation. Indeed, the presence of ubiquitylated proteins and UPS components in inclusions may reflect unsuccessful attempts by the UPS to remove aggregating proteins. Whether the physical presence of inclusions causes cell death or, conversely, whether they are non-toxic and their presence reflects a cellular protective mechanism remains highly controversial.

Conserved signal peptide of Notch3 inhibits interaction with proteasome

“…Inhibition of proteasome function is thought to play a pivotal role in multiple degenerative conditions, such as Alzheimer's, Huntington's, Parkinson's and Lou Gehrig's diseases [20] [21], and could potentially play a role in protein accumulation in CADASIL, which is caused by Notch3 mutations that likely lead to misfolding. Increased misfolding is likely to cause an increase in retrotranslocation [22] [23] [24] of the Notch3 protein to the cytoplasm, which subsequently may permit Notch3/proteasome interactions and proteasome inhibition.…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…Considering the correlation between behavioural deficits and the load of misfolded huntingtin in HD mouse models, the inclusions themselves have been proposed to be on the base of the toxicity in neurons 114,116 . The exact mechanisms of this toxicity, however, remain unsolved but a general impairment of the proteasomal function resulting in proteostasis collapse and cellular death has been proposed 117 . An in vitro study suggested that the proteasome is not able to cleave within PolyQ stretches and the occasional failure of these long undegradable sequences to exit the proteasome may interfere with its function 118 .…”

Molecular Pathways: Targeting Proteasomal Protein Degradation in Cancer

“…However, unlike any of the other proteasome inhibitors (27,36,39,43), NPI-0052 penetrates the blood-brain barrier and inhibits brain proteasome CT-L activity by >90% (36). Abnormalities in the ubiquitinproteasome system have been linked to neurodegenerative diseases (44,45), raising potential safety concerns around long-term treatment with NPI-0052.…”