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Targeted quantification of detergent-insoluble RNA-binding proteins in Alzheimer’s disease reveals disease-specific coaggregation signatures

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 AD brain and that of other dementias. In total, we quantified 870 peptides from 385 detergent-insoluble RNA-binding proteins across 44 cortical tissues including controls, AsymAD, AD, and Parkinson’s Disease (PD). 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 progressively increased in insolubility across progressive AD stages, whereas the RNA splicing module was decreased specifically in PD. Collectively, this work identifies classes of RNA-binding proteins that distinctly co-aggregate in detergent-insoluble fractions across neurodegenerative diseases.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease,Parkinson's Disease

SUBMITTER: Eric Dammer

LAB HEAD: Nicholas T. Seyfried

PROVIDER: PXD022144 | Pride | 2021-03-17

REPOSITORIES: Pride

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Targeted quantification of detergent-insoluble RNA-binding proteins in Alzheimer’s disease reveals disease-specific coaggregation signatures

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