The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution - PubMed (original) (raw)

Review

The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution

Nico P Dantuma et al. Front Mol Neurosci. 2014.

Abstract

The ubiquitin-proteasome system (UPS) has been implicated in neurodegenerative diseases based on the presence of deposits consisting of ubiquitylated proteins in affected neurons. It has been postulated that aggregation-prone proteins associated with these disorders, such as α-synuclein, β-amyloid peptide, and polyglutamine proteins, compromise UPS function, and delay the degradation of other proteasome substrates. Many of these substrates play important regulatory roles in signaling, cell cycle progression, or apoptosis, and their inadvertent stabilization due to an overloaded and improperly functioning UPS may thus be responsible for cellular demise in neurodegeneration. Over the past decade, numerous studies have addressed the UPS dysfunction hypothesis using various model systems and techniques that differ in their readout and sensitivity. While an inhibitory effect of some disease proteins on the UPS has been demonstrated, increasing evidence attests that the UPS remains operative in many disease models, which opens new possibilities for treatment. In this review, we will discuss the paradigm shift that repositioned the UPS from being a prime suspect in the pathophysiology of neurodegeneration to an attractive therapeutic target that can be harnessed to accelerate the clearance of disease-linked proteins.

Keywords: neurodegeneration; proteasome; protein quality control; proteolysis; ubiquitin.

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Figures

Figure 1

Figure 1

Structure and function of common ubiquitin modifications. Ubiquitin may be conjugated to protein substrates as either a monomer or a polymeric chain, in which one of seven internal lysine (Lys) residues of ubiquitin, or the N-terminal methionine, serves as an acceptor for additional ubiquitin moieties. The type of polyubiquitin linkage dictates the topology of the resulting chain. Ubiquitin modifications can regulate protein function or act as a signal in many cellular processes. Examples for functions of monoubiquitylation, and homogenous Lys11-, Lys48-, and Lys63-linked polyubiquitin chains are shown.

Figure 2

Figure 2

Cellular pathways that counteract protein aggregation are ubiquitin-dependent processes. Proteins linked to neurodegenerative diseases, such as α-synuclein, β-amyloid peptide and polyQ proteins, are prone to misfolding and aggregation in the cellular environment. The proteasome, autophagy, and inclusion bodies form a network of quality control systems which reduces levels of misfolded proteins and counteracts aggregation. All three pathways are regulated by ubiquitylation.

Figure 3

Figure 3

Targeting the ubiquitin-proteasome system (UPS) in neurodegenerative disorders using small molecules or engineering approaches. Various events in the UPS can be targeted by compounds in order to stimulate UPS activity. Among those events are accelerating of ubiquitylation by compounds or engineered ubiquitin ligases, inhibition of deubiquitylation, inhibition of protein aggregation so that the proteins remain in a state that is permissible to proteasomal degradation and stimulation of the formation of inclusion bodies which may reduce the load of aggregation-prone proteins and preserve UPS activity.

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