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.

KEYWORDS:

• Amyloid
• Cryo-EM structure
• functional amyloids
• low complexity domain
• Neurodegeneration
• Ribonucleoprotein
• RNA-binding protein

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

A.B.-N. and J.G.-P. performed energy calculations. A.B.-N., J.G.-P. and S.V. reviewed the literature and wrote the manuscript.

Data availability statement

Data sharing does not apply to this article as no new data were created or analysed in this study.

Additional information

Funding

This work was funded by the Spanish Ministry of Science and Innovation (MICINN) PID2019-105017RB-I00 to S.V., by ICREA, ICREA-Academia 2020 and by EU (PhasAge/H2020-WIDESPREAD-2020-5) to S.V. J.G.-P. was supported by the Spanish Ministry of Science and Innovation with a Juan de la Cierva Incorporacion (IJC2019-041039-I). This article is partially based upon work from COST Action ML4NGP, CA21160, supported by COST (European Cooperation in Science and Technology). A.B.-N. was supported by the Catalan Ministry of Research and Universities with a predoctoral grant Joan Oró FI.