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Suppression of NCALD protects against spinal muscular atrophy by restoring impaired endocytosis

ABSTRACT: Spinal muscular atrophy (SMA) is a common genetic motor neuron (MN) disease caused by low levels of the ubiquitously expressed housekeeping survival motor neuron (SMN) protein, whereas concomitant overexpression of plastin 3 (PLS3) protects from SMA. Here we identify neurocalcin delta (NCALD), a neuronal calcium sensor, as a second fully protective SMA modifier, which counteracts SMA pathology when downregulated. We show reduced Ca2+ influx and impaired endocytosis in SMA, which are crucial processes in synaptic vesicle recycling and neurotransmission. Remarkably, both reduced NCALD or increased PLS3 restore endocytosis in cell culture and MN function across species in zebrafish, worm and mouse SMA models, whereas Ca2+ influx remains disturbed. Furthermore, NCALD physically binds clathrin in a Ca2+-dependent manner. We propose that NCALD acts as a Ca2+-regulated inhibitor of endocytosis, and that endocytosis is critically affected in SMA. This finding opens new therapeutic avenues for SMA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58316 | GEO | 2015/01/01

SECONDARY ACCESSION(S): PRJNA251983

REPOSITORIES: GEO

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Suppression of NCALD protects against spinal muscular atrophy by restoring impaired endocytosis

Project description:Spinal muscular atrophy (SMA) is a common genetic motor neuron (MN) disease caused by low levels of the ubiquitously expressed housekeeping survival motor neuron (SMN) protein, whereas concomitant overexpression of plastin 3 (PLS3) protects from SMA. Here we identify neurocalcin delta (NCALD), a neuronal calcium sensor, as a second fully protective SMA modifier, which counteracts SMA pathology when downregulated. We show reduced Ca2+ influx and impaired endocytosis in SMA, which are crucial processes in synaptic vesicle recycling and neurotransmission. Remarkably, both reduced NCALD or increased PLS3 restore endocytosis in cell culture and MN function across species in zebrafish, worm and mouse SMA models, whereas Ca2+ influx remains disturbed. Furthermore, NCALD physically binds clathrin in a Ca2+-dependent manner. We propose that NCALD acts as a Ca2+-regulated inhibitor of endocytosis, and that endocytosis is critically affected in SMA. This finding opens new therapeutic avenues for SMA. Multifactorial design comparing affected patients and unaffected disease carriers against severly affected control group to identify disease modifying transcripts

2015-01-01 | E-GEOD-58316 | biostudies-arrayexpress

Spinal Muscular Atrophy Patient iPSC-derived Motor Neurons Display Altered Proteins at Early Stages of Differentiation

Project description:Spinal muscular atrophy (SMA) is characterized by low levels of survival motor neuron (SMN) protein and loss of motor neurons (MN); however, the underlying mechanism that links SMN deficiency to selective motor neuronal dysfunction is still largely unknown. We present here, for the first time, a comprehensive quantitative mass spectrometry study that covers the development of iPSC-derived MNs from both healthy individuals and SMA patients. We show an altered proteomic signature in SMA already at early stages during MN differentiation, associated with ER to Golgi transport, mRNA splicing and protein ubiquitination, in line with known SMA phenotypes. These alterations in the SMA proteome increase further towards later stages of MN differentiation. In addition, we find differences in altered protein expression between SMA patients, which however, have similar biological functions. Finally, we highlight several known SMN-binding partners as well as proteins associated with ubiquitin-mediated proteolysis and evaluate their expression changes during MN differentiation. Altogether, our work provides a rich resource of molecular events during early stages of MN differentiation, containing potentially therapeutically interesting protein expression profiles for SMA.

2022-02-15 | PXD015115 | Pride

Selective Death in Spinal Muscular Atrophy: Genome-Wide RNA-Seq Using Purified Patient-Derived Motor Neurons

Project description:Spinal Muscular Atrophy (SMA) is well-known to be caused by mutations in the gene Survival of Motor Neuron 1 (SMN1). Because this gene is ubiquitously expressed, it remains poorly understood why motor neurons (MNs) are one of the most affected cell types. To begin to address this question, we carried out RNA-sequencing studies using fixed, antibody-labeled and purified MNs produced from control and SMA patient-derived induced pluripotent stem cells (iPSCs). We found SMA-specific changes in MNs, including hyper-activation of the endoplasmic reticulum (ER) stress pathway and enhanced apoptosis. Functional studies demonstrated that inhibition of ER stress improves overall MN health and survival in vitro even in MNs with low SMN levels. In SMA mice, we show that systemic delivery of an ER stress inhibitor that crosses the blood-brain-barrier led to preservation of MNs in the spinal cord and prolonged survival of these mice. Therefore, our study implies that selective activation of ER stress underlies MN death in SMA. Moreover, the approach we have taken would be broadly applicable to studying disease-prone human cells in heterogeneous cultures. total RNA collected from ES cell and patient ES cell derived spinal motor neurons

2015-09-01 | E-GEOD-69175 | biostudies-arrayexpress

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

Plastin 3 rescues deficient TrkB/BDNF signaling and protects from dysregulations in Ca2+ homeostasis in SMA mouse models

Project description:Spinal muscular atrophy (SMA) is a lethal pediatric neuromuscular disease caused by loss of the Survival Motor Neuron 1 gene (SMN1). Although current therapies focus very efficiently on SMN restoration, the cellular mechanisms underlying the pathological features are not fully understood. Smn-deficient motoneurons tremendously suffer from functional abnormalities leading to affected motoneuron differentiation and maturation. Based on our study, we could illustrate disturbed F-actin-dependent translocation of the Tropomyosin-kinase receptor B (TrkB) to the cell surface of axonal terminals of Smn-deficient motoneurons. This in turn results in impaired Brain-derived neurotrophic factor-induced TrkB activation and downstream signaling. Focusing on the F-actin bundling properties of the protective SMA modifier Plastin 3 revealed that its restoration significantly compensates altered TrkB surface recruitment and activation and ameliorates Cav2.1/2 cluster formation and cellular excitability in Smn-deficient motor axons. Thus, Plastin 3 supports in general two major cellular mechanisms indispensable for development and functional maintenance of motoneurons.

2023-01-05 | GSE197638 | GEO

Gene expression profiling of LMC and MMC motor neurons in SMA mice

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

Next Generation Sequencing of human SMA and healthy control Motor Neurons

Project description:Spinal muscular atrophy (SMA) is a motor neuron (MN) disorder caused by mutations in SMN1. The reasons of MNs selective vulnerability linked to SMN reduction remain unclear. To address this question, we performed deep RNA sequencing on SMA human MNs to detect specific altered splicing/expressed genes and to identify the presence of a common sequence motif in these genes. Many deregulated genes, such as Neurexin and Synaptotagmin families, are implicated in critical MN-function like axonogenesis and synapses. Motif-enrichment analyses of differentially expressed/spliced genes, including Neurexin2 (NRXN2), revealed a common Motif, Motif-7, which is target of SYNCRIP protein. Interestingly, SYNCRIP interacts only with full-length SMN, binding and modulating several MN transcripts, including SMN itself. SYNCRIP overexpression rescued SMA-MNs, due to the consequent increase of SMN and their down-stream target NRXN2, through a positive loop mechanism. SMN/SYNCRIP complex through motif-7 might account for selective MN degeneration and represent a potential therapeutic target.

2018-10-12 | GSE108094 | GEO

STAT3 promotes motor neuron differentiation by collaborating with motor neuron-specific LIM complex

Project description:The motor neuron (MN)–hexamer complex consisting of LIM homeobox 3, Islet-1, and nuclear LIM interactor is a key determinant of motor neuron specification and differentiation. To gain insights into the transcriptional network in motor neuron development, we performed a genome-wide ChIP-sequencing analysis and found that the MN–hexamer directly regulates a wide array of motor neuron genes by binding to the HxRE (hexamer response element) shared among the target genes. Interestingly, STAT3-binding motif is highly enriched in the MN–hexamer–bound peaks in addition to the HxRE. We also found that a transcriptionally active form of STAT3 is expressed in embryonic motor neurons and that STAT3 associates with the MN–hexamer, enhancing the transcriptional activity of the MN–hexamer in an upstream signal-dependent manner. Correspondingly, STAT3 was needed for motor neuron differentiation in the developing spinal cord. Together, our studies uncover crucial gene regulatory mechanisms that couple MN–hexamer and STAT-activating extracellular signals to promote motor neuron differentiation in vertebrate spinal cord.

2013-09-19 | GSE50993 | GEO

Selective Death in Spinal Muscular Atrophy: Genome-Wide RNA-Seq Using Purified Patient-Derived Motor Neurons

2015-09-01 | GSE69175 | GEO

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

2014-09-08 | GSE56284 | GEO