RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer's disease

• Type of Material: Article
• Authors: Isaac Bishof, Emory University; Eric Dammer, Emory University; Duc M. Duong, Emory University; Sean R. Kundinger, Emory University; Marla Gearing, Emory University; James Lah, Emory University; Allan Levey, Emory University; Nicholas Seyfried, Emory University
• Language: English
• Date: 2018-07-13
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Bishof et al.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.RA118.001747
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 293
• Issue: 28
• Start Page: 11047
• End Page: 11066
• Grant/Funding Information: Research reported in this publication was supported in part by the Emory Neuroscience NINDS Core Facilities (Grant P30NS055077) from the National Institutes of Health, NINDS.; This work was supported in part by National Institutes of Health Grants 5R01AG053960 and R21AG054206 (to N. T. S.), Accelerating Medicine Partnership for AD Grant U01AG046161, and Emory Alzheimer's Disease Research Center Grant P50 AG025688.
• Keywords: Science & Technology; INSOLUBLE BRAIN PROTEOME; proteomics; PRION-LIKE DOMAINS; LOW-COMPLEXITY DOMAINS; mass spectrometry (MS); intrinsically disordered protein; protein-protein interaction; MESSENGER-RNA; neurodegeneration; Tau protein (Tau); RNA processing; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; NUCLEAR-LOCALIZATION; AMYOTROPHIC-LATERAL-SCLEROSIS; protein aggregation; NEURODEGENERATIVE DISEASES; FRONTOTEMPORAL LOBAR DEGENERATION; RNA-binding protein; systems biology; TAU; NETWORK APPROACH
• Research Categories: Biology, Microbiology; Chemistry, Biochemistry; Biology, Neuroscience

Abstract

The U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) and other RNA-binding proteins (RBPs) are mislocalized to cytoplasmic neurofibrillary Tau aggregates in Alzheimer’s disease (AD), yet the co-aggregation mechanisms are incompletely understood. U1-70K harbors two disordered low– complexity domains (LC1 and LC2) that are necessary for aggregation in AD brain extracts. The LC1 domain contains highly repetitive basic (Arg/Lys) and acidic (Asp/Glu) residues, referred to as a basic-acidic dipeptide (BAD) domain. We report here that this domain shares many of the properties of the Gln/Asn-rich LC domains in RBPs that also aggregate in neurodegenerative disease. These properties included self-assembly into oligomers and localization to nuclear granules. Co-immunoprecipitations of recombinant U1-70K and deletions lacking the LC domain(s) followed by quantitative proteomic analyses were used to resolve functional classes of U1-70K-interacting proteins that depend on the BAD domain for their interaction. Within this interaction network, we identified a class of RBPs with BAD domains nearly identical to that found in U1-70K. Two members of this class, LUC7L3 and RBM25, required their respective BAD domains for reciprocal interactions with U1-70K and nuclear granule localization. Strikingly, a significant proportion of RBPs with BAD domains had elevated insolubility in the AD brain proteome. Furthermore, we show that the BAD domain of U1-70K can interact with Tau from AD brains but not from other tauopathies. These findings highlight a mechanistic role for BAD domains in stabilizing RBP interactions and in potentially mediating co-aggregation with the pathological AD–specific Tau isoforms.