The multifaceted functions of β-arrestins and their therapeutic potential in neurodegenerative diseases

Abstract

Arrestins are multifunctional proteins that regulate G-protein-coupled receptor (GPCR) desensitization, signaling, and internalization. The arrestin family consists of four subtypes: visual arrestin1, β-arrestin1, β-arrestin2, and visual arrestin-4. Recent studies have revealed the multifunctional roles of β-arrestins beyond GPCR signaling, including scaffolding and adapter functions, and physically interacting with non-GPCR receptors. Increasing evidence suggests that β-arrestins are involved in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease (PD). β-arrestins physically interact with γ-secretase, leading to increased production and accumulation of amyloid-beta in AD. Furthermore, β-arrestin oligomers inhibit the autophagy cargo receptor p62/SQSTM1, resulting in tau accumulation and aggregation in FTD. In PD, β-arrestins are upregulated in postmortem brain tissue and an MPTP model, and the β2AR regulates SNCA gene expression. In this review, we aim to provide an overview of β-arrestin1 and β-arrestin2, and describe their physiological functions and roles in neurodegenerative diseases. The multifaceted roles of β-arrestins and their involvement in neurodegenerative diseases suggest that they may serve as promising therapeutic targets.

β-arrestins: unveiling their crucial role in neurodegenerative diseases

Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis are neurodegenerative diseases impacting millions worldwide. Recent research has identified a significant association between these diseases and beta-arrestin, a regulatory protein that interacts with G-protein-coupled receptors (GPCRs). GPCRs play crucial roles in numerous biological processes and are the focus of many drug therapies. This review article provides a comprehensive summary of the established functions of beta-arrestins and underscores recent findings linking beta-arrestins to neurodegenerative diseases. Furthermore, it explores novel therapeutic avenues by targeting beta-arrestins in a manner that avoids disrupting their vital interactions with GPCRs. Researchers believe this strategy could lead to more efficient and specific treatments for these debilitating diseases.