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RNA-binding proteins with prion-like domains in health and disease.
Biochem J. 2017 04 07; 474(8):1417-1438.BJ

Abstract

Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid-liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribonucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.

Authors+Show Affiliations

Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A. Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A.Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A. jshorter@mail.med.upenn.edu. Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

28389532

Citation

Harrison, Alice Ford, and James Shorter. "RNA-binding Proteins With Prion-like Domains in Health and Disease." The Biochemical Journal, vol. 474, no. 8, 2017, pp. 1417-1438.
Harrison AF, Shorter J. RNA-binding proteins with prion-like domains in health and disease. Biochem J. 2017;474(8):1417-1438.
Harrison, A. F., & Shorter, J. (2017). RNA-binding proteins with prion-like domains in health and disease. The Biochemical Journal, 474(8), 1417-1438. https://doi.org/10.1042/BCJ20160499
Harrison AF, Shorter J. RNA-binding Proteins With Prion-like Domains in Health and Disease. Biochem J. 2017 04 7;474(8):1417-1438. PubMed PMID: 28389532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RNA-binding proteins with prion-like domains in health and disease. AU - Harrison,Alice Ford, AU - Shorter,James, Y1 - 2017/04/07/ PY - 2017/01/09/received PY - 2017/02/06/revised PY - 2017/02/09/accepted PY - 2017/4/9/entrez PY - 2017/4/9/pubmed PY - 2017/5/17/medline KW - RNA-binding proteins KW - disaggregase KW - neurodegeneration KW - phase separation KW - prion-like domain SP - 1417 EP - 1438 JF - The Biochemical journal JO - Biochem J VL - 474 IS - 8 N2 - Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid-liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribonucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration. SN - 1470-8728 UR - https://www.unboundmedicine.com/medline/citation/28389532/RNA_binding_proteins_with_prion_like_domains_in_health_and_disease_ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BCJ20160499 DB - PRIME DP - Unbound Medicine ER -