Recent pharmacological insights on abating toxic protein species burden in neurological disorders: Emphasis on 26S proteasome activation

Protein homeostasis (proteostasis) refers to the plethora of mechanisms that safeguard the proper folding of the newly synthesized proteins. It entails various intricately regulated cues that demolish the toxic protein species to prevent their aggregation. The ubiquitin-proteasome system (UPS) is recognized as a salient protein degradation system, with a substantial role in maintaining proteostasis. However, under certain circumstances the protein degradation capacity of the UPS is overwhelmed, leading to the accumulation of misfolded proteins. Several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington disease, and amyotrophic lateral sclerosis are characterized with the presence of protein aggregates and proteinopathy. Accordingly, enhancing the 26S proteasome degradation activity might delineate a pioneering approach in targeting various proteotoxic disorders. Regrettably, the exact molecular approaches that enhance the proteasomal activity are still not fully understood. Therefore, this review aimed to underscore several signaling cascades that might restore the degradation capacity of this molecular machine. In this review, we discuss the different molecular components of the UPS and how 26S proteasomes are deleteriously affected in many neurodegenerative diseases. Moreover, we summarize different signaling pathways that can be utilized to renovate the 26S proteasome functional capacity, alongside currently known druggable targets in this circuit and various classes of proteasome activators. [Display omitted] •Proteasomal impairment is a common feature in many neurological disorders.•cAMP-PKA and cGMP-PKG signaling axes activation elevates the proteasomal capacity.•The proteasomal dysfunction might be reverted by MAPKs signaling pathway modulation.•SUMOylation inhibitors are emerging as potential proteasomal modulators.•Nrf2 pathway activators might devote a bright hope for proteasomal activation.