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

2021 ◽  
Vol 14 ◽  
Author(s):  
Qi Guo ◽  
Eric B. Dammer ◽  
Maotian Zhou ◽  
Sean R. Kundinger ◽  
Marla Gearing ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Splicing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splicing Factors ◽  
Nuclear Speckles ◽  
Spliceosome Assembly ◽  
Network Analyses

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.

DT-03-02: Viewing neurodegeneration beyond the tangle: The role of RNA binding proteins in Alzheimer's disease

2013 ◽  
Vol 9 ◽  
pp. P847-P847
Author(s):  
Benjamin Wolozin ◽  
Tara Vanderweyde ◽  
Liqun Liu-Yesucevitz ◽  
Alpaslan Dedeoglu ◽  
Leonard Petrucelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins

scholarly journals The Sub-Nuclear Localization of RNA-Binding Proteins in KSHV-Infected Cells

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1958
Author(s):  
Ella Alkalay ◽  
Chen Gam Ze Letova Refael ◽  
Irit Shoval ◽  
Noa Kinor ◽  
Ronit Sarid ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Viral Infections ◽  
Rna Binding Proteins ◽  
Nuclear Periphery ◽  
Lytic Cycle ◽  
Splicing Factors ◽  
Nuclear Speckles ◽  
Viral Rnas ◽  
Infected Cells

RNA-binding proteins, particularly splicing factors, localize to sub-nuclear domains termed nuclear speckles. During certain viral infections, as the nucleus fills up with replicating virus compartments, host cell chromatin distribution changes, ending up condensed at the nuclear periphery. In this study we wished to determine the fate of nucleoplasmic RNA-binding proteins and nuclear speckles during the lytic cycle of the Kaposi’s sarcoma associated herpesvirus (KSHV). We found that nuclear speckles became fewer and dramatically larger, localizing at the nuclear periphery, adjacent to the marginalized chromatin. Enlarged nuclear speckles contained splicing factors, whereas other proteins were nucleoplasmically dispersed. Polyadenylated RNA, typically found in nuclear speckles under regular conditions, was also found in foci separated from nuclear speckles in infected cells. Poly(A) foci did not contain lncRNAs known to colocalize with nuclear speckles but contained the poly(A)-binding protein PABPN1. Examination of the localization of spliced viral RNAs revealed that some spliced transcripts could be detected within the nuclear speckles. Since splicing is required for the maturation of certain KSHV transcripts, we suggest that the infected cell does not dismantle nuclear speckles but rearranges their components at the nuclear periphery to possibly serve in splicing and transport of viral RNAs into the cytoplasm.

scholarly journals Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Pamela J. McMillan ◽  
Timothy J. Strovas ◽  
Misa Baum ◽  
Brooke K. Mitchell ◽  
Randall J. Eck ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Transgenic Mice ◽  
Brain Tissue ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Scaffold Protein ◽  
Nuclear Speckles ◽  
Nuclear Speckle ◽  
C Elegans

AbstractSeveral conserved nuclear RNA binding proteins (sut-1, sut-2, and parn-2) control tau aggregation and toxicity in C. elegans, mice, and human cells. MSUT2 protein normally resides in nuclear speckles, membraneless organelles composed of phase-separated RNAs and RNA-binding proteins that mediate critical steps in mRNA processing including mRNA splicing. We used human pathological tissue and transgenic mice to identify Alzheimer’s disease-specific cellular changes related to nuclear speckles. We observed that nuclear speckle constituent scaffold protein SRRM2 is mislocalized and accumulates in cytoplasmic lesions in AD brain tissue. Furthermore, progression of tauopathy in transgenic mice is accompanied by increasing mislocalization of SRRM2 from the neuronal nucleus to the soma. In AD brain tissue, SRRM2 mislocalization associates with increased severity of pathological tau deposition. These findings suggest potential mechanisms by which pathological tau impacts nuclear speckle function in diverse organisms ranging from C. elegans to mice to humans. Future translational studies aimed at restoring nuclear speckle homeostasis may provide novel candidate therapeutic targets for pharmacological intervention.

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

2018 ◽  
Vol 293 (28) ◽  
pp. 11047-11066 ◽  
Author(s):  
Isaac Bishof ◽  
Eric B. Dammer ◽  
Duc M. Duong ◽  
Sean R. Kundinger ◽  
Marla Gearing ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins

O2-02-05: RNA-BINDING PROTEINS WITH MIXED CHARGE DOMAINS SELF-ASSEMBLE AND AGGREGATE IN ALZHEIMER'S DISEASE

2006 ◽  
Vol 14 (7S_Part_11) ◽  
pp. P612-P612
Author(s):  
Isaac J. Bishof ◽  
Eric B. Dammer ◽  
Duc Duong ◽  
Marla Gearing ◽  
James J. Lah ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins

scholarly journals P4-520: TAU OLIGOMERS MEDIATE AGGREGATION OF RNA-BINDING PROTEINS MUSASHI1- AND MUSASHI2-INDUCING NUCLEAR MEMBRANE ALTERATION IN ALZHEIMER'S DISEASE

2019 ◽  
Vol 15 ◽  
pp. P1513-P1513
Author(s):  
Mauro Montalbano ◽  
Salome McAllen ◽  
Urmi Sengupta ◽  
Nemil Bhatt ◽  
Anna Ellsworth ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nuclear Membrane ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Tau Oligomers

scholarly journals RNA-binding proteins with mixed charge domains self-assemble and aggregate in Alzheimer’s Disease

2018 ◽  
Author(s):  
Isaac Bishof ◽  
Eric B. Dammer ◽  
Duc M. Duong ◽  
Marla Gearing ◽  
James J. Lah ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Significant Proportion ◽  
Mass Spectrometry Analysis ◽  
Rna Granules ◽  
Intrinsically Disordered ◽  
Small Nuclear Ribonucleoprotein

ABSTRACTU1 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 understanding of the mechanisms that cause their aggregation is limited. Many RBPs that aggregate in neurodegenerative diseases self-assemble into RNA granules through intrinsically disordered low complexity (LC) domains. We report here that a LC domain within U1-70K of mixed charge, containing highly repetitive complementary repeats of basic (R/K) and acidic (D/E) residues, shares many of the same properties of the Q/N-rich LC domains found in the RBPs TDP-43 and FUS. These properties include the ability to self-assemble into oligomers, and to form nuclear granules. To analyze the functional roles of the U1-70K LC domains, we performed co-immunoprecipitation and quantitative mass spectrometry analysis of recombinant U1-70K and deletions lacking the C-terminal LC domain(s). A network-driven approach resolved functional classes of U1-70K interacting proteins that showed dependency on the U1-70K LC domain(s) for their interaction. This included structurally similar RBPs, such as LUC7L3 and RBM25, which require their respective mixed charge domains for reciprocal interactions with U1-70K and for participation in nuclear RNA granules. Strikingly, a significant proportion of RBPs with mixed charge domains have elevated insolubility in AD brain proteome compared to controls. Furthermore, we show that the mixed charge LC domain of U1-70K can interact with Tau from AD brain. These findings highlight mechanisms for mixed charge domains in stabilizing RBP interactions and in potentially mediating co-aggregation with pathological Tau isoforms in AD.

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