Ubiquitin-Proteasome System in Neurodegenerative Disorders - PubMed (original) (raw)

Ubiquitin-Proteasome System in Neurodegenerative Disorders

Geeta Rao et al. J Drug Metab Toxicol. 2015.

Abstract

Cellular proteostasis is a highly dynamic process and is primarily carried out by the degradation tools of ubiquitin-proteasome system (UPS). Abnormalities in UPS function result in the accumulation of damaged or misfolded proteins which can form intra- and extracellular aggregated proteinaceous deposits leading to cellular dysfunction and/or death. Deposition of abnormal protein aggregates and the cellular inability to clear them have been implicated in the pathogenesis of a number of neurodegenerative disorders such as Alzheimer's and Parkinson's. Contrary to the upregulation of proteasome function in oncogenesis and the use of proteasome inhibition as a therapeutic strategy, activation of proteasome function would serve therapeutic objectives of treatment of neurodegenerative diseases. This review describes the current understanding of the role of the proteasome in neurodegenerative disorders and potential utility of proteasomal modulation therein.

Keywords: Brain pathologies; Neurodegenerative disorders; Proteasome modulators; Proteostasis; Ubiquitin-proteasome system.

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Figures

Figure 1:

Figure 1:. Ubiquitin-proteasome system (UPS).

UPS involves ubiquitination and proteolytic degradation of ubiquitinated proteins. Ubiquitin is first attached to the target protein via a cascade involving three distinct enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). The ubiquitinated substrate is recognized, unfolded, and deubiquitinated by the 19S regulatory particle. The unfolded protein enters the 20S catalytic particle where it is degraded by the β1 (trypsin-like activity), β2 (caspase-like activity) and β5 (chymotrypsin-like activity) subunits.

Figure 2:

Figure 2:. Various assemblies of proteasome.

The proteasome is a mono-capped or bi-capped cylindrical structure. The cylindrical core (20S or CP) is formed by two different types of protein subunits, α and β, which are arranged in four stacked heptameric rings enclosing a central cavity. The proteasome core particle can be capped with 19S or 11S activator complexes (a third activator complex Blm10/PA200 is not shown).

Figure 3:

Figure 3:. UPS dysregulation in neurodegenerative disorders.

Almost all neurodisorders of contemporary interest are characterized by imbalanced UPS function, indicating the possible role of modulators of UPS as adjunct therapy.

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