Integrative analyses of splicing in the aging brain: role in susceptibility to Alzheimer’s Disease

T, Raj; Li, Yang; Wong, Garrett; Ramdhani, Satesh; Wang, Y; B, Ng; Wang, M; Gupta, Ishaan; Haroutunian,; Ee, Schadt; Zhang, B; Young‐Pearse, Tracy L.; Mostafavi, Sara; Sklar, Pamela; Bennett, David A.; Pl, De Jager

doi:10.1101/174565

Cited by 13 publications

(12 citation statements)

References 66 publications

(104 reference statements)

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“…We next asked whether PD-associated variants were enriched among molecular (including expression, splicing, histone, and DNA methylation) quantitative trait loci (QTLs) in dorsolateral prefrontal cortex (DLFPC) 21,22 and immune cell-types 5,23 ( Fig. 1c).…”

Section: Heritability Enrichment Of Expressed Genes Identifies Pd-relmentioning

confidence: 99%

“…Individuals were genotyped on Illumina Human 610 Quad custom arrays.The gene expression data is available via https://ega-archive.org/studies/EGAS00001000411. (4) ROS/MAP RNA-seq data generation was previously described in22,21 . ROS/MAP is a prospective cohort of aging individuals, where individuals are healthy at enrollment and 38% have clinical Alzheimer's disease at the time of death.…”

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confidence: 99%

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Prioritizing Parkinson’s Disease genes using population-scale transcriptomic data

Wong

Humphrey

et al. 2017

Preprint

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Genome-wide association studies (GWAS) have identified over 41 susceptibility loci associated with late-onset Parkinson's Disease (PD) but identifying putative causal genes and the underlying mechanisms remains challenging. To address this, we leveraged large-scale transcriptomic datasets to prioritize genes that are likely to affect PD. We found 29 gene associations in peripheral monocytes, and 44 gene associations whose expression or differential splicing in prefrontal cortex is associated with PD. This includes many novel genes but also known associations such as MAPT, for which we found that variation in exon 3 splicing explains the common genetic association. Genes identified in our analyses are more likely to interact physically with known PD genes and belong to the same or related pathways including lysosomal and innate immune function. Overall, our study provides a strong foundation for further mechanistic studies that will elucidate the molecular drivers of PD.

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Section: Heritability Enrichment Of Expressed Genes Identifies Pd-relmentioning

confidence: 99%

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confidence: 99%

Prioritizing Parkinson’s Disease genes using population-scale transcriptomic data

Wong

Humphrey

et al. 2017

Preprint

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“…However, the precise gene-regulatory mechanisms and molecular pathways involved in AD progression remain to be elucidated. Case-control studies of differential gene expression in large postmortem brain cohorts have identified multiple genes and regulatory elements associated by AD [3][4][5] . The gene regulatory networks of these differentially-expressed genes have revealed promising associated genes for AD 3,4 , However, interpretation of case-control differential expression is challenging because it requires accounting for reverse causation of disease on gene expression, biological confounding, and technical confounding.…”

Section: Introductionmentioning

confidence: 99%

A Bayesian approach to mediation analysis predicts 206 causal target genes in Alzheimer’s disease

Park

et al. 2017

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Characterizing the intermediate phenotypes, such as gene expression, that mediate genetic effects on complex diseases is a fundamental problem in human genetics. Existing methods utilize genotypic data and summary statistics to identify putative disease genes, but cannot distinguish pleiotropy from causal mediation and are limited by overly strong assumptions about the data. To overcome these limitations, we develop Causal Multivariate Mediation within Extended Linkage disequilibrium (CaMMEL), a novel Bayesian inference framework to jointly model multiple mediated and unmediated effects relying only on summary statistics. We show in simulation that CaMMEL accurately distinguishes between mediating and pleiotropic genes unlike existing methods. We applied CaMMEL to Alzheimer's disease (AD) and found 206 causal genes in sub-threshold loci (p < 10 −4 ). We prioritized 21 genes which mediate at least 5% of local genetic variance, disrupting innate immune pathways in AD.

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“…U1-70K is normally nuclear, but is found mislocalized to cytoplasmic Tau-immunoreactive neurofibrillary aggregates in AD neurons (6), which may contribute to a loss of spliceosome function given recently identified RNA splicing deficits in the disease (8). Mislocalization of other RBPs contributes to neurodegenerative disease (55,56).…”

Section: Discussionmentioning

confidence: 99%

“…For example, U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) and other core components of the spliceosome complex form detergent-insoluble aggregates in both sporadic and familial human cases of AD (5)(6)(7). Furthermore, RNA-seq analysis from AD and control brains revealed a significant accumulation of unspliced pre-mRNA disease related transcripts in AD consistent with a loss of U1-spliceosome function (7,8). Currently, our knowledge of the specific mechanisms underlying U1-70K aggregation is limited.…”

Section: Introductionmentioning

confidence: 99%

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

Bishof

Dammer

Duong

et al. 2018

Preprint

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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 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 coimmunoprecipitation 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 coaggregation with pathological Tau isoforms in AD. INTRODUCTION The molecular processes that contribute to neurodegenerative diseases are not well understood. Recent observations suggest that numerous neurodegenerative diseases are promoted by the accumulation of RNA-binding protein (RBP) aggregates (1-3). This includes Alzheimer's disease (AD), where pathological RNA-protein aggregates are often, but not exclusively, associated with Tau neurofibrillary . CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/243014 doi: bioRxiv preprint first posted online Jan. 4, 2018; Mixed Charge RNA binding proteins aggregate in AD 2 tangles in brain (4). For example, U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) and other core components of the spliceosome complex form detergent-insoluble aggregates in both sporadic and familial human cases of AD (5-7). Furthermore, RNA-seq analysis from AD and control brains revealed a significant accumulation of unspliced pre-mRNA disease related transcripts in AD consistent with a loss of U1-spliceosome function (7,8). Currently, our knowledge of the specific mechanisms underlying U1-70K aggregation is limited. This has proved to be a barrier to developing cellular models that wou...

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Integrative analyses of splicing in the aging brain: role in susceptibility to Alzheimer’s Disease

Cited by 13 publications

References 66 publications

Prioritizing Parkinson’s Disease genes using population-scale transcriptomic data

Prioritizing Parkinson’s Disease genes using population-scale transcriptomic data

A Bayesian approach to mediation analysis predicts 206 causal target genes in Alzheimer’s disease

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

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