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Multi-omic analysis identifies APC/C-mediated degradation of SMN in neurons

ABSTRACT: Spinal muscular atrophy (SMA) due to loss-of-function of SMN protein is associated with severe loss of voluntary muscle control and is a leading inherited cause of infant mortality. SMA treatments will benefit from in-depth knowledge of functional pathways disrupted in disease and identification of SMN modulators. Here, we present a comprehensive temporal profile of proteogenomic expression patterns in developing mouse spinal cords (Δ7 model), alongside endpoint analyses of human spinal and ventral root tissues in SMA disease, identifying targets for assessing disease progression and treatment response. SMA disease results in development-associated deficiencies in transcription, translation initiation, intracellular transport, and protein folding, and diminished RNA translation efficiency for proteins important in axon development/myelination. The broad impact of SMN deficiency prompted the search for co-regulated proteins that modulate SMN protein levels, resulting in identification of the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin ligase as a potential modulator of SMN protein stability. Functional studies of APC/C showed that both SMN and HuD are specific interactors of the APC/C in neurons and that selective APC/C inhibition significantly limited SMN and HuD degradation. Finally, we demonstrate that APC/C inhibition rescues motor axon defects characteristic of SMA in a zebrafish model of SMA disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE128129 | GEO | 2022/01/18

REPOSITORIES: GEO

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Ribosome profiling of SMN-primed ribosomes and active ribosome profiling from brains of a mouse model of severe SMA

Project description:Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, with an incidence of around 1 in 6,000-10,000 live births. SMA is caused by low levels of full-length survival of motor neuron protein (SMN). We demonstrate that SMN binds to ribosomes and that this interaction is tissue-dependent. We performed ribosome profiling analyses on lysates from P5 wild-type mouse brains exposed to RNase I, from which we isolated SMN-primed ribosomes by immunoprecipitation. SMN-primed ribosomes are preferentially positioned within the first five codons of a set of mRNAs which are enriched for translational enhancer sequences in the 5’UTR and rare codons at the beginning of their coding sequence. These SMN-specific mRNAs are associated with neurogenesis, lipid metabolism, ubiquitination, chromatin regulation and translation. Additionally, we analyzed the positioning of active ribosomes using the Active-RiboSeq method based on RiboLace and compared early symptomatic SMA mouse brains to age-matched controls. We found that loss of SMN induces ribosome depletion, especially at the beginning of the coding sequence of SMN-specific mRNAs, leading to impairment of proteins involved in motor neuron function and stability. Keywords: motor neuron disease, spinal muscular atrophy, SMA, SMN, SMN1, survival of motor neuron, SMN-primed ribosome profiling, translation, RiboLace, Ribo-Seq, active translation, ribosome heterogeneity

2020-08-11 | GSE154106 | GEO

Transcriptome and translatome profiling from brains of a mouse model of severe SMA

Project description:Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, with an incidence of around 1 in 6,000-10,000 live births. SMA is caused by low levels of full-length survival of motor neuron protein (SMN). Approximately 95% of SMA cases in humans are caused by homozygous deletion of SMN1, with a smaller number caused by discrete mutations within the gene. In concert with other RNA binding proteins, SMN forms complexes both in the nucleus and the cytoplasm of neurons. As such, SMN protein has housekeeping roles in the assembly of ribonucleoprotein (RNP) complexes. In addition, SMN localises to dendrites, synapses and axons in vivo and in vitro, where it is part of messenger RNP (mRNP) complexes with well-known roles in the transport of mRNA. These cellular processes are tightly linked to local translation, suggesting that SMN may play a pivotal role in its regulation. We employed next generation sequencing (NGS) to identify and quantify RNAs associated with polysomes (POL-Seq) in parallel with total cytoplasmic RNA (RNA-Seq) in an established mouse model of severe SMA at both early and late-symptomatic stages. This approach enables the simultaneous identification of variations in RNA populations at both translatome (RNAs engagement with polysomes) and transcriptome (steady state cytoplasmic RNAs) levels. Keywords: motor neuron disease, spinal muscular atrophy, SMA,SMN, translation, polysome profiling, POL-Seq, RNA-Seq

2017-10-24 | GSE102204 | GEO

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Project description:The deficiency of Survival motor neuron (SMN) protein causes the motor neuron disease spinal muscular atrophy (SMA). One of the cellular hallmarks of motor neuron diseases is the reduction in number of nuclear bodies (NBs) positive for the SMN protein. Owing to its ubiquitous expression, the consequences of SMN reduction can be studied in SMA patient fibroblasts. In previous studies, we described the beneficial effects of flunarizine on SMN-positive NBs both in fibroblasts of SMA patients and in spinal motor neurons of an SMA mouse model. Given that nuclear bodies are involved in RNA metabolism, here the goals are to make a proof-of-concept that genes modulated by flunarizine at the RNA levels can be identified and confirmed at the protein levels in SMA patient fibroblasts. Indeed, RNA-Seq analysis reveals that TXNIP is the most reduced by a 4-hr flunarizine treatment of SMA patient fibroblasts. This result is confirmed by RT-qPCR. Moreover, immunoblot analyses also shows a marked reduction of TXNIP at the protein levels in flunarizine-treated SMA fibroblasts.

2020-04-30 | GSE145146 | GEO

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Project description:Spinal muscular atrophy (SMA) is a neurodegenerative disease which exhibits selective motor neuron death caused by a ubiquitous deficiency of the survival motor neuron (SMN) protein. It remains unclear how the ubiquitous reduction of SMN lead to death in selective motor neuron pools. Medial motor neuron columns (MMC) are vulnerable, whereas lateral motor columns (LMC) are resistant to motor neuron death in SMA. Here we performed microarray and pathway analysis comparing cholera toxin subunit B (CTb) labeled vulnerable MMC and resistant LMC of pre-symptomatic SMA with corresponding motor neuron columns of control mice to identify pathways involved in selective motor neuron death in SMA. WT is FVB. SMN is Delta7 (SMNΔ7;SMN2;Smn-) on a FVB background.

2017-12-12 | GSE81245 | GEO

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2021-02-01 | GSE149391 | GEO

Expression profiles of skeletal muscle from Taiwanese Smn-/-;SMN2 spinal muscular atrophy mouse model treated with Pip6a-PMO

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2020-05-14 | GSE150517 | GEO

Transcriptome profiling of severe spinal muscular atrophy mouse embryonic stem cell-derived motor neurons

Project description:Proximal spinal muscular atrophy (SMA) is an early onset, autosomal recessive motor neuron disease caused by loss of or mutation in SMN1 (survival motor neuron 1). Despite understanding the genetic basis underlying this disease, it is still not known why motor neurons (MNs) are selectively affected by the loss of the ubiquitously expressed SMN protein. Using a mouse embryonic stem cell (mESC) model for severe SMA, the RNA transcript profiles (transcriptomes) between control and severe SMA (SMN2+/+;mSmn-/-) mESC-derived MNs were compared in this study using massively parallel RNA sequencing (RNA-Seq). The MN differentiation efficiencies between control and severe SMA mESCs were similar. RNA-Seq analysis identified 3094 upregulated and 6964 downregulated transcripts in SMA mESC-derived MNs when compared against control cells. Pathway and network analysis of the differentially expressed RNA transcripts showed that pluripotency and cell proliferation transcripts were significantly increased in SMA MNs while transcripts related to neuronal development and activity were reduced. The differential expression of selected transcripts such as Crabp1, Crabp2 and Nkx2.2 was validated in a second mESC model for SMA as well as in the spinal cords of low copy SMN2 severe SMA mice. Furthermore, the levels of these selected transcripts were restored in high copy SMN2 rescue mouse spinal cords when compared against low copy SMN2 severe SMA mice. These findings suggest that SMN deficiency affects processes critical for normal development and maintenance of MNs. RNA profiles were generated from FACS-purified control and SMA mESC-derived motor neurons (n=3/genotype) by deep sequencing using Illumina HighSeq 2500

2014-09-08 | E-GEOD-56284 | biostudies-arrayexpress

Quantitative proteomic analysis of Survival Motor Neuron (SMN) missense mutants in Drosophila

Project description:Spinal Muscular Atrophy (SMA) is a devastating neuromuscular disease caused by hypomorphic loss of function in the Survival Motor Neuron (SMN) protein. SMA presents across broad spectrum of disease severity. Unfortunately, vertebrate models of intermediate SMA have been difficult to generate and are thus unable to address key aspects of disease etiology. To address these issues, we developed a Drosophila model system that recapitulates the full range of SMA severity, allowing studies of pre-onset biology as well as late-stage disease processes. In this study, TMT-based quantitative proteomic profiling was performed on mild and intermediate Drosophila models of SMA to elucidate proteins and pathways that contribute to the disease. Using this approach, we elaborated a role for the SMN complex in the regulation of innate immune signaling.

2024-04-11 | PXD046801 | Pride

The Bap1-SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates survival of motor neurons

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in the survival of motor neuron (SMN) gene. Although the primary manifestation of SMA is degeneration of motor neurons in a dying-back manner, deficient SMN intrinsic to motor neurons does not cause severe motor neuron loss, as is the case in SMA mouse models. Thus, the involvement of non-neuronal cells in the pathogenesis of SMA has been suggested. Here, we report that a novel subset of fibro-adipogenic progenitors expressing Dpp4 (Dpp4+ FAPs) is required for the survival of motor neurons, in which BRCA1-associating protein 1 (Bap1) is crucial for the stabilization of SMN by preventing its ubiquitination-dependent degradation. Inactivation of Bap1 in FAPs decreased SMN levels and accompanied degeneration of the neuromuscular junction, leading to dying-back loss of motor neurons and muscle atrophy, reminiscent of SMA pathogenesis. Overexpression of ubiquitination-resistant SMN variant, SMNK186R, in Bap1-null FAPs completely prevented neuromuscular degenerations. In addition, transplantation of Dpp4+ FAPs, but not Dpp4- FAPs, completely rescued neuromuscular defects in the mutant mice. Our data revealed that Bap1-mediated stabilization of SMN in Dpp4+ FAPs is crucial for the survival of motor neurons and provided a new therapeutic approach to treat SMA.

2022-06-30 | GSE190426 | GEO

Neurochondrin interacts with the SMN protein suggesting a novel mechanism for Spinal Muscular Atrophy pathology.

Project description:Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative condition caused by reduction in functional Survival Motor Neurones Protein (SMN). SMN has been implicated in transport of mRNA in neural cells for local translation. We previously identified microtubule-dependant mobile vesicles rich in SMN and SmB, a member of the Sm family of snRNP-associated proteins, in neural cells. By comparing the interactomes of SmB and SmN, a neural-specific Sm protein, we now show that the essential neural protein neurochondrin (NCDN) interacts with Sm proteins and SMN in the context of mobile vesicles in neurites. NCDN has roles in protein localisation in neural cells, and in maintenance of cell polarity. NCDN is required for the correct localisation of SMN, suggesting they may both be required for formation and transport of trafficking vesicles. NCDN may have potential as a therapeutic target for SMA together with, or in place of, those targeting SMN expression

2018-03-15 | PXD008710 | Pride

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