G-quadruplexes and associated proteins in aging and Alzheimer’s disease

Abstract

Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer’s disease (AD). Alzheimer’s disease is characterized by progressive cognitive decline, memory loss, and neuropsychiatric and behavioral symptoms, accounting for most of the reported dementia cases. This disease is now becoming a major challenge and burden on modern society, especially with the aging population. Over the last few decades, a significant understanding of the pathophysiology of AD has been gained by studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, and neuroinflammation. This review focuses on the role of non-canonical secondary structures of DNA/RNA G-quadruplexes (G4s, G4-DNA, and G4-RNA), G4-binding proteins (G4BPs), and helicases, and their roles in aging and AD. Being critically important for cellular function, G4s are involved in the regulation of DNA and RNA processes, such as replication, transcription, translation, RNA localization, and degradation. Recent studies have also highlighted G4-DNA’s roles in inducing DNA double-strand breaks that cause genomic instability and G4-RNA’s participation in regulating stress granule formation. This review emphasizes the significance of G4s in aging processes and how their homeostatic imbalance may contribute to the pathophysiology of AD.

The Role of Tau Pathology in Alzheimer’s Disease and Down Syndrome

“…Another event that occurs with normal aging and AD is the accumulation of RNA and DNA quadruplexes [ 56 ], which have recently been shown to contribute to aging-related neuronal dysfunction and cell loss. G-Quadruplex (G4) DNA and RNA (RG4) are non-canonical secondary nucleic acid structures that have multiple roles in vital cellular processes, both in health and disease [ 56 , 57 ]. G4s are involved in regulating both DNA and RNA processes, including replication, transcription, and translation, and RG4s have been shown to particularly accumulate during cellular stress conditions [ 57 ].…”

“…G-Quadruplex (G4) DNA and RNA (RG4) are non-canonical secondary nucleic acid structures that have multiple roles in vital cellular processes, both in health and disease [ 56 , 57 ]. G4s are involved in regulating both DNA and RNA processes, including replication, transcription, and translation, and RG4s have been shown to particularly accumulate during cellular stress conditions [ 57 ]. A recent meta-analysis combining genome-wide association studies (GWAS) expanded the number of AD-risk loci, but most disease-associated variants reside in non-protein coding regions of the genome, such as in long non-coding (lnc) RNAs [ 58 ].…”

The Role of Tau Pathology in Alzheimer’s Disease and Down Syndrome

“…Another event that occurs with normal aging and AD is the accumulation of RNA and DNA quadruplexes [56], which have recently been shown to contribute to agingrelated neuronal dysfunction and cell loss. G-Quadruplex (G4) DNA and RNA (RG4) are non-canonical secondary nucleic acid structures that have multiple roles in vital cellular processes, both in health and disease [56,57]. G4s are involved in regulating both DNA and RNA processes, including replication, transcription, and translation, and RG4s have been shown to particularly accumulate during cellular stress conditions [57].…”

Small-molecule-based regulation of gene expression in human astrocytes upon both positive and negative actuations of G-quadruplex control systems

“…), cancers and aging phenotypes. [15][16][17][18][19] Chemical biologists aspire to subs7tute proteins with small molecules, which offer greater prac7cal convenience. They have developed numerous G4 molecular chaperones, or G4 ligands, 20 which have been used to idemonstrate the existence and prevalence of both DNA and RNA G4s in human cells; 21 iiprovide insights into the regula7on of gene expression at both transcrip7onal and transla7onal levels, 6,22 and iiiadvance chemotherapeu7c strategies that leverage G4s as gene7c tools to impede the progression of diseases, especially cancers.…”