Mutations in human prion-like domains: pathogenic but not always amyloidogenic

Abstract

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These proteins typically contain prion-like domains of low complexity (PrLDs or LCDs) that govern their assembly into either functional or pathological amyloid fibrils. To date, over 60 mutations targeting the LCDs of hnRNPs have been identified and associated with a spectrum of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). The cryo-EM structures of pathological and functional fibrils formed by different hnRNPs have been recently elucidated, including those of hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, and FUS. In this review, we discuss the structural features of these amyloid assemblies, placing particular emphasis on scrutinizing the impact of prevalent disease-associated mutations mapping within their LCDs. By performing systematic energy calculations, we reveal a prevailing trend of destabilizing effects induced by these mutations in the amyloid structure, challenging the traditionally assumed correlation between pathogenicity and amyloidogenic propensity. Understanding the molecular basis of this discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases.

Investigation of the Circular Transcriptome in Alzheimer’s Disease Brain

“…GFAP correlates with Aβ plaques and acts as a marker of astrogliosis in AD brain (O'Connor A et al 2023 ). Moreover, advanced technology has unveiled that mutations of heterogenous nuclear ribonucleoproteins (hnRNPs) might play a crucial role as a regulatory factor in AD (Bartolomé-Nafría A et al 2024 ). For instance, mutations on the prion-like domains of low complexity of hnRNPs were identified to exhibit association of amyloid fibril with neurodegenerative disease through accumulating toxicity to disorder (Lim L et al 2016 ).…”