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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE197638 | GEO | 2023/01/05

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

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

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple and parallel data driven approaches for the development of novel treatments for use in combination with SMN restoration therapies.

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Project description:Neurotransmission defects and motoneuron degeneration are hallmarks of Spinal Muscular Atrophy, a monogenetic disease caused by the deficiency of the SMN protein. In the present study, we show that systemic application of R-Roscovitine - a Cav2.1 / Cav2.2 channel modifier and a Cyclin-dependent kinase 5 (Cdk-5) inhibitor - significantly improved survival of SMA mice. In addition, R-Roscovitine increased Cav2.1 channel density and sizes of the motor endplates. In vitro, R-Roscovitine restored axon lengths and growth cone sizes of Smn-deficient motoneurons corresponding to enhanced spontaneous Ca2+ influx and elevated Cav2.2 channel cluster formations independent of its capability to inhibit Cdk-5. Acute application of R-Roscovitine at the neuromuscular junction significantly increased evoked neurotransmitter release, the frequency of spontaneous miniature potentials, and lowered the activation threshold of silent terminals. These data indicate that R-Roscovitine improves Ca2+ signaling and Ca2+ homeostasis in Smn-deficient motoneurons which is generally crucial for motoneuron differentiation, maturation, and function.

2020-01-28 | GSE112771 | GEO

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

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2022-06-30 | GSE190426 | GEO

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

2015-01-01 | GSE58316 | GEO

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2017-12-12 | GSE81245 | GEO

Gain of toxic function by long-term SMN overexpression in the sensory-motor circuit.

Project description:The neurodegenerative disease spinal muscular atrophy (SMA) is a leading genetic cause of infant death caused by deficiency in the survival motor neuron (SMN) protein. Currently approved SMA treatments aim to restore SMN, but the potential for expression of SMN beyond physiological levels is a unique feature of AAV9-SMN gene therapy. Here, we show that long-term AAV9-mediated SMN overexpression in mouse models induces dose-dependent, late-onset motor dysfunction associated with loss of proprioceptive synapses and neurodegeneration. Mechanistically, aggregation of overexpressed SMN in the cytoplasm of motor circuit neurons sequesters components of small nuclear ribonucleoproteins (snRNPs), leading to splicing dysregulation and widespread transcriptome abnormalities with prominent signatures of neuroinflammation and innate immune response. Thus, long-term SMN overexpression can interfere with its normal activity in RNA regulation and trigger SMA-like pathogenic events through toxic gain of function mechanisms. These unanticipated, SMN-dependent and neuron-specific liabilities of AAV9-SMN warrant further evaluation of the long-term safety of gene therapy in SMA.

2021-02-01 | GSE149391 | GEO

The small-molecule flunarizine in spinal muscular atrophy patient fibroblasts impacts on the Gemin components of the SMN complex and RNA-binding proteins relevant to motor neuron diseases

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

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

Trancriptional regulation by axonal SMN on motor neuron cells

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2012-01-07 | E-MEXP-3402 | biostudies-arrayexpress

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