Advances in Proteasome Enhancement by Small Molecules

Abstract

The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. In this review, we discuss the structure of proteasome and how proteasome’s proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.

Apoptosis and (in) Pain—Potential Clinical Implications

“…The UPP is relevant in neural development and brain structure and also in maintenance of their functions, and is implicated in synaptic plasticity, formation, and maintenance of memory. Recently, it was found that the dysfunction of this proteasomal degradation pathway leads to changes in cell death by apoptosis in diverse cell types and may be implicated in the pathogenesis of several diseases, either through hypofunction, as in neurodegenerative diseases [ 61 , 62 ], or by hyperfunction, as in the case of neoplastic diseases [ 57 , 62 ]. More recently, ubiquitin system dysfunction has been implicated in chronic pain, mainly in neuropathic pain (NP) and inflammatory pain, through ubiquitination modified protein receptors and ion channels to affect synaptic activity and efficiency [ 57 ].…”

Healthspan improvement and anti-aggregation effects induced by a marine-derived structural proteasome activator

“…It is increasingly accepted that proteasome activation may act protectively against the progression of various proteinopathies [ 25 , 65 ]. This is not surprising as diminished proteasome activity and reduced protein expression levels of various proteasome subunits have been detected in various in vitro and in vivo AD models, as well as in the brain samples of AD patients [ 66 , 67 ].…”

Development of a Cell-Based AlphaLISA Assay for High-Throughput Screening for Small Molecule Proteasome Modulators

“… 3 , 7 The main protease of the UPS is the enzymatic core particle: the 20S proteasome. 3 , 4 , 7 , 8 The 20S proteasome is barrel-shaped and composed of four stacked heptameric rings where the two α-rings sandwich the two β-rings. 7 , 8 The β-rings house the three catalytic sites: the β 1 (caspase-like), β 2 (trypsin-like), and β 5 (chymotrypsin-like).…”

“…Proteostasis is a highly orchestrated balance between protein synthesis and degradation. , This process is regulated through the cross-coordination of several cellular pathways, including the ubiquitin–proteasome system (UPS). − The UPS is a vital protein degradation system and is responsible for the degradation of most intracellular and soluble proteins. , The main protease of the UPS is the enzymatic core particle: the 20S proteasome. ,,, The 20S proteasome is barrel-shaped and composed of four stacked heptameric rings where the two α-rings sandwich the two β-rings. , The β-rings house the three catalytic sites: the β 1 (caspase-like), β 2 (trypsin-like), and β 5 (chymotrypsin-like). − Access to these catalytic sites is controlled by the amino termini pendant groups of the α-rings that interlace to form a gate to the interior of the 20S core particle. Regulatory particles, like the 19S cap, can dock into pockets between the α-rings and induce an open-gate 20S conformation.…”