The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease.

Kundlik Gadhave,Nityanand Bolshette,Alexandru Istrate,Maria Balea,Cristiana Trandafir,Mangala Lahkar,Rohit Pardeshi,Krishan Thakur,Ashutosh Ahire,Dafin F Muresanu,Sahabuddin Ahmed

doi:10.1111/jcmm.12817

Abstract

The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age‐related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS‐related therapies for AD.

Highlights

The ubiquitin proteasomal system – Ubiquitination and deubiquitination – The 26S proteasome – The ubiquitin proteasomal pathway in neurodegenerative disorders Treatment strategies for Alzheimer’s disease – Therapies targeting misfolding– Therapies targeting the different quality control systems of the cell – UPS components as potential therapeutic targets in AD management – Importance of UPP in the management of Alzheimer’s disease – Recent therapeutic developments Future prospects Conclusion AbstractThe cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones
The UPS degrades more than 80% of normal and abnormal intracellular proteins [18]
E2-25k/Hip-2 induction is required for neuronal cell death under amyloid beta (Ab) toxicity

Summary

Introduction

Biosynthesized proteins often misfold because of destabilizing mutations, stress or metabolic changes [1] and cannot perform their. Ubiquitinated protein aggregates cause UPS dysfunction or structural changes in protein substrates that prevent their recognition and degradation This loss of degradation has pleiotropic effects on neurons, such as cell death, degeneration and synaptic malfunction [50]. E2-25k/Hip-2 induction is required for neuronal cell death under Ab toxicity It inhibits proteasome activity and promotes the accumulation of ubiquitin conjugates, which increases the levels of apoptosis signal regulating kinase-1/C-Jun N-terminal kinase and leads to Ab neurotoxicity. UBB+1 is selectively expressed in neurons and competes with normal ubiquitin for binding to proteasomal target proteins It interacts with E2-25k/Hip-2 to inhibit the 26S proteasome and block ubiquitin-dependent proteasomal proteolysis [61, 119]. As ubiquitin chain trimming can promote or inhibit proteasomal degradation, future studies should identify whether IU1 inhibits other DUBs or proteases in human cells [27]

Findings

Conclusion