Targeted Quantification of Detergent-Insoluble RNA-Binding Proteins in Human Brain Reveals Stage and Disease Specific Co-aggregation in Alzheimer's Disease

• Authors: Qi Guo, Emory University; Eric Dammer, Emory University; Maotian Zhou, Emory University; Sean R. Kundinger, Emory University; Marla Gearing, Emory University; James Lah, Emory University; Allan Levey, Emory University; Joshua M. Shulman, Baylor College of Medicine; Nicholas Seyfried, Emory University
• Journal Title: Frontiers in Molecular Neuroscience
• Volume: Volume 14
• Publisher: Frontiers Media SA | 2021-03-18, Pages 623659-623659
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3389/fnmol.2021.623659
• Subjects: Biology, Neuroscience; Chemistry, Biochemistry; Health Sciences, Pathology; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; amyloid beta-protein; tau; RNA-binding proteins; Parkinson’ s disease; Alzheimer’ parallel reaction monitoring; mass spectrometry; human brains; Frontotemporal lobar degeneration; Quantitative analysis; Alpha synuclein; Lewy bodies; TAU; Beta; Neurodegeneration; Aggregation; Diagnosis; Proteome

Abstract

Core spliceosome and related RNA-binding proteins aggregate in Alzheimer’s disease (AD) brain even in early asymptomatic stages (AsymAD) of disease. To assess the specificity of RNA-binding protein aggregation in AD, we developed a targeted mass spectrometry approach to quantify broad classes of RNA-binding proteins with other pathological proteins including tau and amyloid beta (Aβ) in detergent insoluble fractions from control, AsymAD, AD and Parkinson’s disease (PD) brain. Relative levels of specific insoluble RNA-binding proteins across different disease groups correlated with accumulation of Aβ and tau aggregates. RNA-binding proteins, including splicing factors with homology to the basic-acidic dipeptide repeats of U1-70K, preferentially aggregated in AsymAD and AD. In contrast, PD brain aggregates were relatively depleted of many RNA-binding proteins compared to AsymAD and AD groups. Correlation network analyses resolved 29 distinct modules of co-aggregating proteins including modules linked to spliceosome assembly, nuclear speckles and RNA splicing. Modules related to spliceosome assembly and nuclear speckles showed stage-specific enrichment of insoluble RBPs from AsymAD and AD brains, whereas the RNA splicing module was reduced specifically in PD. Collectively, this work identifies classes of RNA-binding proteins that distinctly co-aggregate in detergent-insoluble fractions across the specific neurodegenerative diseases we examined.