Noncoding RNAs in neurodegeneration

Salta, Evgenia; Strooper, Bart De

doi:10.1038/nrn.2017.90

Cited by 135 publications

(113 citation statements)

References 247 publications

(226 reference statements)

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“…The magnitude of interactions shown by network analyses, further complicated by high between-tissue variability, presents one of today's largest obstacles in microRNA (miRNA) research. Because miRNAs exert individual effects of low impact, the outcome of their cooperative action can be more adequately represented by a network approach than by traditional molecular interaction studies (Salta and De Strooper, 2017). Although experimental validations are necessary, they often significantly exceed the scope of scientific publications, even for one single miRNA.…”

Section: Discussionmentioning

confidence: 99%

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

et al. 2019

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Graphical Abstract Highlights d Single-cell transcriptomes reveal a unique profile of cortical cholinergic neurons d Female-and male-derived cells show distinct neurokineinduced miRNA responses d Differentially enriched microRNA families constitute a selforganizing network d Integrative analysis identifies mir-10/mir-199 regulators of cholinergic function SUMMARYRNA sequencing analyses are often limited to identifying lowest p value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large-scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA sequencing of human male-and female-originating cell lines, and connectomics of transcription factor and microRNA interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. Although these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method reveals the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130family neurokine controllers of immune function interlinked by microRNAs. This approach may open additional perspectives for seeking biomarkers and therapeutic targets in other transmitter systems and diseases.

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Section: Discussionmentioning

confidence: 99%

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

et al. 2019

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“…The magnitude of interactions shown by network analyses, further complicated by high betweentissue variability, presents one of today's largest obstacles in microRNA research. As miRs exert individual effects of low impact, the outcome of their cooperative action can be more adequately represented by a network approach than by traditional molecular interaction studies (Salta and De Strooper, 2017). While experimental validations are necessary, they often significantly exceed the scope of scientific publications even for one single miR.…”

Section: Discussionmentioning

confidence: 99%

Integrative transcriptomics reveals sexually dimorphic microRNA control of the cholinergic/neurokine interface in schizophrenia and bipolar disorder

Lobentanzer

Hanin

Klein

et al. 2019

Preprint

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135 words): RNA-sequencing analyses are often limited to identifying lowest p-value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA-sequencing of human male-and female-originated cell lines, and connectomics of transcription factor-and microRNA-interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. While these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method explicates the differences between afflicted men and women, and identifies diseaseaffected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function, interlinked by microRNAs. This approach may open new perspectives for seeking biomarkers and therapeutic targets, also in other transmitter systems and diseases.Manuscript (Erta et al., 2012): the gp130 co-receptor (also known as IL6ST, IL-6 signal transducer), and the LIF-receptor. Gp130-family neurokines unite properties of neurotrophic (e.g. on dopaminergic neurons) and immunogenic nature, both prominent facets in the molecular etiology of SCZ and BD (Harrison, 2015) and in cholinergic signaling (Stanke et al., 2006). Neurokines can activate JAK1/2, TYK2 and STAT1/3/5A/5B (Rawlings, 2004), affecting neurotransmission as well as immunity. However, to the best of our knowledge, their roles in SCZ/BD were not yet studied.SCZ/BD hallmarks also involve circadian perturbations. The cholinergic-catecholaminergic imbalance in BD (Van Enkhuizen et al., 2015) follows variable transcriptionally-regulated rhythms (e.g. CLOCK, ARNTL, RORA), and affected individuals exhibit decreased REM latency (the duration from onset of sleep to the first rapid eye movement phase) and increased vulnerability for disease that can be modulated by muscarinic agonists/antagonists (Ising et al., 2005). Correspondingly, the muscarinic M1/M3 receptor genes are essential for REM sleep (Niwa et al., 2018), and sleep deprivation exerts short-term antidepressant effects (Wu and Bunney, 1990), reduced cortical ACh levels (Boonstra et al., 2007), and vast transcriptional changes in basal forebrain cholinergic neurons (Nikonova et al., 2017).The quantitative measurement of disease-relevance of individual perturbed genes is a common methodological problem in transcriptomic analyses. To reduce complexity, transcripts are often filtered by their p-values, leading to bias towards few highly expressed and differentially regulated genes. This does not agree with a polygenic model where each component contributes a small effect. To alleviate this bias while still attempting the necessary complexity reduction, we developed an integrative approach of multiple perspectives. Jerusalem and Andreas Meisel, Berlin and to Dr. Ester Bennett, Jerusalem ...

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“…Cryptic or skiptic DNA elements may be associated with disease in humans but not exist in mice, such as the cryptic polyadenylation site in STATHMIN2 (a neuronal growth associated factor) that is present in sporadic and some genetic forms of ALS (26) . Non-coding changes also modulate disease outcomes: for example, by 2017 more than 3,000 different genome-wide association studies (GWAS) had reported >30,000 SNP-disease associations, the vast majority of which lie in non-coding regions (27), indicating the importance of gene regulation in disease, including neurodegenerative disease (25,28).…”

Section: Mice and Humans Are Differentmentioning

confidence: 99%

Mouse models of neurodegeneration: Know your question, know your mouse

Fisher

Bannerman

2019

Sci. Transl. Med.

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Overline: Neurodegenerative Disease Single Sentence Summary:We can now create an unprecedented set of mouse models for understanding neurodegeneration and we need to carefully consider which model best fits our research question and how to learn from the variability within and between studies. AbstractMany mutant mouse strains have been developed to investigate neurodegenerative diseases, but variability among mouse studies has led to questioning of the value of these mouse models. Here, we appraise various mouse models for dissecting neurodegenerative mechanisms and emphasise the importance of asking appropriate scientific questions and understanding variability among and within studies. In therapeutics research, we suggest that not embracing this variability in mouse models may contribute to translational failure in human patients.

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Noncoding RNAs in neurodegeneration

Cited by 135 publications

References 247 publications

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

Integrative transcriptomics reveals sexually dimorphic microRNA control of the cholinergic/neurokine interface in schizophrenia and bipolar disorder

Mouse models of neurodegeneration: Know your question, know your mouse

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