Key role of SMN/SYNCRIP and RNA-Motif 7 in spinal muscular atrophy: RNA-Seq and motif analysis of human motor neurons

Rizzo, Federica; Nizzardo, Monica; Vashisht, Shikha; Molteni, Erika; Melzi, Valentina; Taiana, Michela; Salani, Sabrina; Santonicola, Pamela; Schiavi, Elia Di; Bucchia, Monica; Bordoni, Andreina; Faravelli, Irene; Bresolin, Nereo; Comi, Giacomo Pietro; Pozzoli, Uberto; Corti, Stefania

doi:10.1093/brain/awy330

Cited by 34 publications

(40 citation statements)

References 60 publications

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“…We analyzed mRNA expression of four independent D2KO motor neuron cultures, four D10KO (clone G4) motor neuron cultures and eight independent cultures of the parental control motor neurons. Comparison of our parental motor neuron RNA sequencing dataset by principal component analysis (PCA) to available human iPSC-motor neuron datasets (GSE108094 (Rizzo et al, 2019), GSE121069 (Nijssen et al, 2018)) and laser captured post mortem human motor neuron datasets (GSE76220 (Batra et al, 2016), GSE76514 (Nichterwitz et al, 2016), GSE93939 (Allodi et al, 2019)) showed tight clustering of our 8 samples together, supporting consistent, high-quality differentiation conditions of our cultures ( Figure 4A). Interestingly, PCA of all of our samples alone showed that the expression profiles of D2KO and D10KO motor neurons complete overlapped and were separate from parental control motor neurons ( Figure 4B).…”

Section: Chchd10 and Chchd2 Knockout Motor Neurons Have Overlapping Tsupporting

confidence: 70%

“…RNA-seq data from the motor neurons in this study were contrasted to publicly available datasets of other human iPSC derived motor neurons; GSE108094 (Rizzo et al, 2019) and GSE121069 (Nijssen et al, 2018) as well as laser captured motor neurons; GSE76220 (Batra et al, 2016), GSE76514 (Nichterwitz et al, 2016) and GSE93939 (Allodi et al, 2019). The same analysis procedures (trimming, mapping and read counting) were applied to the reference samples as for our dataset.…”

Section: Rna Sequencingmentioning

confidence: 99%

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Chchd10 or Chchd2 are not Required for Human Motor Neuron Differentiation In Vitro but Modify Synaptic Transcriptomes

Harjuhaahto

Rasila

MOLCHANOVA

et al. 2019

Preprint

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Mitochondrial intermembrane space proteins CHCHD2 and CHCHD10 have roles in diseases affecting motor neurons such as amyotrophic lateral sclerosis, spinal muscular atrophy and axonal neuropathy and in Parkinson's disease, and form a complex of unknown function. Here we address the importance of these two proteins in human motor neurons. We show that gene edited human induced pluripotent stem cells (iPSC) lacking either CHCHD2 or CHCHD10 are viable and can be differentiated into functional motor neurons that fire spontaneous and evoked action potentials.Knockout iPSC and motor neurons sustain mitochondrial ultrastructure and show reciprocal compensatory increases in CHCHD2 or CHCHD10. Knockout motor neurons have largely overlapping transcriptome profiles compared to isogenic control line, in particular for synaptic gene expression. Our results show that absence of CHCHD2 or CHCHD10 does not disrupt functionality, but induces similar modifications in human motor neurons. Thus pathogenic mechanisms may involve loss of synaptic function.

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Section: Chchd10 and Chchd2 Knockout Motor Neurons Have Overlapping Tsupporting

confidence: 70%

Section: Rna Sequencingmentioning

confidence: 99%

Chchd10 or Chchd2 are not Required for Human Motor Neuron Differentiation In Vitro but Modify Synaptic Transcriptomes

Harjuhaahto

Rasila

MOLCHANOVA

et al. 2019

Preprint

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“…Among the complex members, HNRNPU was previously identified as one of five top-ranked RNA binding proteins, showing significant alterations in the motor neurons, cerebellum and spinal cords of ALS patients compared to the control, and co-localizes with cytoplasmic TDP-43 aggregates [64,65]. Moreover, we observed in SALS2 motor cortexes vs. control a down-regulation of SYNCRIP, whose overexpression was previously found to ameliorate spinal muscular atrophy pathological phenotypes [66].…”

Section: Crd-mediated Mrna Stability Complexsupporting

confidence: 56%

Splicing Players Are Differently Expressed in Sporadic Amyotrophic Lateral Sclerosis Molecular Clusters and Brain Regions

Cognata

Gentile

Aronica

et al. 2020

Cells

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Splicing is a tightly orchestrated process by which the brain produces protein diversity over time and space. While this process specializes and diversifies neurons, its deregulation may be responsible for their selective degeneration. In amyotrophic lateral sclerosis (ALS), splicing defects have been investigated at the singular gene level without considering the higher-order level, involving the entire splicing machinery. In this study, we analyzed the complete spectrum (396) of genes encoding splicing factors in the motor cortex (41) and spinal cord (40) samples from control and sporadic ALS (SALS) patients. A substantial number of genes (184) displayed significant expression changes in tissue types or disease states, were implicated in distinct splicing complexes and showed different topological hierarchical roles based on protein–protein interactions. The deregulation of one of these splicing factors has a central topological role, i.e., the transcription factor YBX1, which might also have an impact on stress granule formation, a pathological marker associated with ALS.

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“…In mammals, different domains mediate the interaction of SYNCRIP with different effectors, which renders SYNCRIP a wide range of functions including circadian regulation [45][46][47], neuronal morphogenesis [48][49][50], and stress response [51]. Misregulation of SYNCRIP has been reported in neurodegenerative diseases [52,53], psychiatric disorders [54,55], and cancer [56,57]. In flies, studies have shown that Syp is required for different developmental phenotypes, such as oogenesis [28], maintaining a normal structure and function of synapses at the neuromuscular junction in larvae [29,30], and determining neuron/glia cell fates [31,32].…”

Section: Discussionmentioning

confidence: 99%

RNA-binding protein Syncrip regulates Starvation-Induced Hyperactivity in adultDrosophila

Chi

Liu

et al. 2020

Preprint

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How to respond to starvation determines fitness. One prominent behavioral response is increased locomotor activities upon starvation, also known as Starvation-Induced Hyperactivity (SIH). SIH is paradoxical as it promotes food seeking but also increases energy expenditure. Either too much or too little SIH would impair fitness. Despite its importance, the genetic contributions to SIH as a behavioral trait remains unexplored. Here, we examined SIH in the Drosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association studies. We identified 27 significant loci, corresponding to 18 genes, significantly associated with SIH in adult Drosophila. Gene enrichment analyses indicated that genes encoding ion channels and mRNA binding proteins (RBPs) were most enriched in SIH. We are especially interested in RBPs because they provide a potential mechanism to quickly change protein expression in response to environmental challenges. Using RNA interference, we validated the role of Syp in regulating SIH. Syp encodes Syncrip, an RBP. While ubiquitous knockdown of Syp led to lethality during development, adult flies with neuron specific Syp knockdown were viable and exhibited decreased SIH. Using the Temporal and Regional Gene Expression Targeting (TARGET) system, we further confirmed the role of Syp in adult neurons in regulating SIH. Lastly, RNA-seq analyses revealed that Syp was alternatively spliced under starvation while its expression level was unchanged. Together, this study not only demonstrates genetic contributions to SIH as an important behavioral trait but also highlights the significance of RBPs and post-transcriptional processes in regulating SIH.

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Key role of SMN/SYNCRIP and RNA-Motif 7 in spinal muscular atrophy: RNA-Seq and motif analysis of human motor neurons

Cited by 34 publications

References 60 publications

Chchd10 or Chchd2 are not Required for Human Motor Neuron Differentiation In Vitro but Modify Synaptic Transcriptomes

Chchd10 or Chchd2 are not Required for Human Motor Neuron Differentiation In Vitro but Modify Synaptic Transcriptomes

Splicing Players Are Differently Expressed in Sporadic Amyotrophic Lateral Sclerosis Molecular Clusters and Brain Regions

RNA-binding protein Syncrip regulates Starvation-Induced Hyperactivity in adultDrosophila

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