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This review explores the roles of RNA-binding proteins in the pathophysiology of Alzheimer’s disease.

April 22, 2026ACS Pharmacology & Translational Science0 citations

Roles of RNA-Binding Nuclear Proteins in Alzheimer’s Disease Pathophysiology

SKSandeep KumarIndian Institute of Technology Bhilai AUArun UpadhyayIndian Institute of Technology Bhilai

Key Points

This review explores the roles of RNA-binding proteins in the pathophysiology of Alzheimer’s disease.
Review of recent literature on RNA-binding proteins and their role in Alzheimer's disease
Proteomic study identifying specific RNA-binding proteins associated with amyloid
Discussion of the implications of these proteins in gene expression and RNA processing
Identified three RNA-binding proteins that interact with amyloid β, suggesting a role in AD pathology
Highlighted SRSF2's role in tau exon splicing and its potential impact on AD
Discussed the dysfunction of RNA-associated nuclear proteins and their effect on RNA processing in AD pathways

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive decline. Pathologically, AD is characterized by the accumulation of amyloid β (Aβ) monomers that may generate oligomers or fibrils in the extracellular space and inside the neurons. With time, the oligomers and fibrils aggregate into insoluble plaques, which may trigger a cascade of molecular events. These include altering gene expression at a broader level, implicating cross-talk with the nuclear machinery, including transcription. There is now emerging evidence implicating the role of RNAs and other nuclear proteins in AD pathogenesis, especially those associated with RNA splicing and ribonucleoproteins, which, along with post-transcriptional modifications, give rise to multiple functional proteoforms. Notably, RBPs themselves exist as multiple proteoforms, adding complexity to the proteome involved in AD. Therefore, in this review, we limit the discussion to the canonical protein forms of RBPs already established to have some role in AD pathophysiology. Recently, our proteomic study identified three such RBPs (SRSF2, hnRNPH1, and hnRNPA2B1) copurifying with amyloid, suggesting a possible interaction with Aβ and contribution to AD pathology. SRSF2 is a splicing factor involved in tau exon splicing, while hnRNPH1 and hnRNPA2B1 are both heterogeneous nuclear RBPs (hnRNPs) involved in mRNA processing. Some of the other hnRNPs have previously been implicated in AD and tau pathology. This review focuses on some of the recent evidence that suggests a possible involvement of RNA-associated nuclear proteins in dysregulation of widespread RNA processing affecting the AD pathogenesis pathways. We discuss how their dysfunction could modulate Aβ and tau-associated changes with an emphasis on understanding the linkage between nuclear RNA machinery and AD pathophysiology. Understanding this crosstalk may offer new insights into our understanding of AD and could provide RNA-centric therapeutic avenues.

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