Splicing alterations in healthy aging and disease

Angarola, Brittany; Anczuków, Olga

doi:10.1002/wrna.1643

Cited by 29 publications

(28 citation statements)

References 363 publications

(527 reference statements)

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“…Diverse splicing defects occur in accelerated aging (progeria) and vascular aging. Changes in the activity of splicing factors and in the production of key splice variants may impact cellular senescence and the aging phenotype [23,65].…”

Section: Pathophysiology Of Mds-how Much Aging?mentioning

confidence: 99%

Is Myelodysplasia a Consequence of Normal Aging?

2021

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Purpose of Review To review available data on the relationship of MDS and aging and to address the question if biological changes of (premature) aging are a prerequisite for the development of MDS. Recent Findings Whereas the association of MDS with advanced age and some common biologic features of aging and MDS are well established, additional evidence for both, especially on the role of stem cells, the stem cell niche, and inflammation, has been recently described. Summary Biologically, many but not all drivers of aging also play a role in the development and propagation of MDS and vice versa. As a consequence, aging contributes to the development of MDS which can be seen as an interplay of clonal disease and normal and premature aging. The impact of aging may be different in specific MDS subtypes and risk groups.

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Section: Pathophysiology Of Mds-how Much Aging?mentioning

confidence: 99%

Is Myelodysplasia a Consequence of Normal Aging?

2021

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“…Two major risk factors for atherosclerosis are also linked to increased Ptbp1 expression: senescence and integrin-mediated adhesions to fibronectin. Increased Ptbp1 expression has been observed with age and in senescent cells 27,33 . Aging is arguably the single greatest risk factor for atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) is Required for Immune Priming of the Endothelium in Atherogenic Disturbed Flow Conditions

et al. 2021

Preprint

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NFkB mediated endothelial activation drives leukocyte recruitment and atherosclerosis, in part through upregulation of adhesion molecules Icam1 and Vcam. The endothelium is primed for cytokine activation of NFkB by exposure to low and disturbed blood flow (LDF) in vivo and by LDF or static conditions in cultured cells. While priming leads to an exaggerated expression of Icam1 and Vcam following cytokine stimulation, the molecular underpinnings are not fully understood. We showed that alternative splicing of genes regulating NFkB signaling occurs during priming, but the functional implications of this are not known. We hypothesize that the regulation of splicing by RNA-binding splice factors is critical for priming. Here, we perform a CRISPR screen in cultured aortic endothelial cells to determine whether splice factors active in the response to LDF participate in endothelial cell priming. Using Icam1 and Vcam induction by TNFalpha stimulation as a marker of priming, we identify polypyrimidine tract binding protein (Ptbp1) as a required splice factor. Ptbp1 expression is increased and its motifs are enriched nearby alternatively spliced exons in endothelial cells exposed to LDF in vivo in a platelet dependent manner, indicating its induction by early innate immune cell recruitment. At a mechanistic level, deletion of Ptbp1 inhibited NFkB nuclear translocation and transcriptional activation. These changes coincided with altered splicing of key components of the NFkB signaling pathway that were similarly altered in the LDF response. However, these splicing and transcriptional changes could be restored by expression of human PTBP1 cDNA in Ptbp1 deleted cells. In vivo, endothelial specific deletion of Ptbp1 reduced myeloid cell infiltration at regions of LDF in atherosclerotic mice. In human coronary arteries, PTBP1 expression correlates with expression of TNF pathway genes and amount of plaque. Together, our data suggest that Ptbp1, which is activated in the endothelium by innate immune cell recruitment in regions of LDF, is required for priming of the endothelium for subsequent NFkB activation and myeloid cell recruitment in vascular inflammation.

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“…Alternative splicing of RNAs persists across life span, affecting more than a third of genes linked to neural function in human brains [ 7 ]. Mounting evidence has shown that significant changes in alternative splicing occur during aging progression and neurodegenerative diseases [ 11 ]. However, how these splicing changes affect cognition upon progression of aging and age-related neurodegenerative diseases remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that age-dependent RNA binding protein-mediated alternative splicing is responsible for alterations in synaptic structure and function during aging progression. BACE1 , which encodes β-secretase 1 that catalyzes amyloid precursor protein into β-amyloid (Aβ), undergoes extensive alternative splicing upon aging [ 11 , 12 ]. As a result, full-length BACE1 shows an age-dependent increase, resulting in a rise in BACE1 level and a consequent accumulation of Aβ in the brain [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Nuclear speckle specific hnRNP D-like prevents age- and AD-related cognitive decline by modulating RNA splicing

Zhang

Jin

et al. 2021

Mol Neurodegeneration

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Background Aberrant alternative splicing plays critical role in aging and age-related diseases. Heterogeneous nuclear ribonucleoproteins (hnRNPs) reportedly regulate RNA splicing process. Whether and how hnRNPs contribute to age-related neurodegenerative diseases, especially Alzheimer’s disease (AD), remain elusive. Methods Immunoblotting and immunostaining were performed to determine expression patterns and cellular/subcellular localization of the long isoform of hnRNP D-like (L-DL), which is a hnRNP family member, in mouse hippocampus. Downregulation of L-DL in WT mice was achieved by AAV-mediated shRNA delivery, followed by memory-related behavioural tests. L-DL interactome was analysed by affinity-precipitation and mass spectrometry. Alternative RNA splicing was measured by RNA-seq and analyzed by bioinformatics-based approaches. Downregulation and upregulation of L-DL in APP/PS1 mice were performed using AAV-mediated transduction. Results We show that L-DL is specifically localized to nuclear speckles. L-DL levels are decreased in the hippocampus of aged mouse brains and downregulation of L-DL impairs cognition in mice. L-DL serves as a structural component to recruit other speckle proteins, and regulates cytoskeleton- and synapse-related gene expression by altering RNA splicing. Mechanistically, these splicing changes are modulated via L-DL-mediated interaction of SF3B3, a core component of U2 snRNP, and U2AF65, a U2 spliceosome protein that guides U2 snRNP’s binding to RNA. In addition, L-DL levels are decreased in APP/PS1 mouse brains. While downregulation of L-DL deteriorates memory deficits and overexpression of L-DL improves cognitive function in AD mice, by regulating the alternative splicing and expression of synaptic gene CAMKV. Conclusions Our findings define a molecular mechanism by which hnRNP L-DL regulates alternative RNA splicing, and establish a direct role for L-DL in AD-related synaptic dysfunction and memory decline.

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Splicing alterations in healthy aging and disease

Cited by 29 publications

References 363 publications

Is Myelodysplasia a Consequence of Normal Aging?

Is Myelodysplasia a Consequence of Normal Aging?

Splice Factor Polypyrimidine tract-binding protein 1 (Ptbp1) is Required for Immune Priming of the Endothelium in Atherogenic Disturbed Flow Conditions

Nuclear speckle specific hnRNP D-like prevents age- and AD-related cognitive decline by modulating RNA splicing

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