Synaptic defects in type I spinal muscular atrophy in human development

Martínez-Hernández, Rebeca; Bernal, Sara; Also-Rallo, Eva; Alías, Laura; Barceló, Montserrat; Hereu, Marta; Esquerda, Josep E.; Tizzano, Eduardo F.

doi:10.1002/path.4080

Cited by 78 publications

(60 citation statements)

References 52 publications

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“…NMJ defects are first detectable at postnatal day 5 (P5), including presynaptic defects of terminal arborization and intermediate neurofilament aggregation in MNs, poor postsynaptic organization of AChRs in muscle, as well as reduced synaptic vesicle density and release at the NMJ (7)(8)(9). Importantly, similar NMJ defects have been reported in type I (the most severe type) SMA human fetuses (10). SMA MNs have also been shown to be hyperexcitable and loss of proprioceptive synapses on the somata, and proximal dendrites of SMA MNs (MN deafferentation) occurs no later than P4 (11)(12)(13).…”

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confidence: 84%

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Zhang

Pinto

Wan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

161

140

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The motor neuron (MN) degenerative disease, spinal muscular atrophy (SMA) is caused by deficiency of SMN (survival motor neuron), a ubiquitous and indispensable protein essential for biogenesis of snRNPs, key components of pre-mRNA processing. However, SMA's hallmark MN pathology, including neuromuscular junction (NMJ) disruption and sensory-motor circuitry impairment, remains unexplained. Toward this end, we used deep RNA sequencing (RNA-seq) to determine if there are any transcriptome changes in MNs and surrounding spinal cord glial cells (white matter, WM) microdissected from SMN-deficient SMA mouse model at presymptomatic postnatal day 1 (P1), before detectable MN pathology (P4-P5). The RNA-seq results, previously unavailable for SMA at any stage, revealed cell-specific selective mRNA dysregulations (∼300 of 11,000 expressed genes in each, MN and WM), many of which are known to impair neurons. Remarkably, these dysregulations include complete skipping of agrin's Z exons, critical for NMJ maintenance, strong upregulation of synapse pruning-promoting complement factor C1q, and down-regulation of Etv1/ER81, a transcription factor required for establishing sensory-motor circuitry. We propose that dysregulation of such specific MN synaptogenesis genes, compounded by many additional transcriptome abnormalities in MNs and WM, link SMN deficiency to SMA's signature pathology.transcriptome perturbations | Z+ (neuronal) agrin | C1q complex S pinal muscular atrophy (SMA) is an autosomal recessive motor neuron (MN) degenerative disease and a leading genetic cause of infant mortality (1, 2). SMA is caused by deletions or point mutations in the survival of motor neurons 1 gene (SMN1) (3), exposing a splicing defect in a duplicated gene (SMN2), which produces predominantly exon 7-skipped mRNA (SMNΔ7) (4). This in turn creates a degron that destabilizes the SMNΔ7 protein, resulting in reduced SMN levels (SMN deficiency) (5). SMA pathology has been extensively characterized in patients as well as a widely used SMA mouse model (6). Major morphological and biochemical deficits have been found at neuromuscular junctions (NMJs) and sensory-motor synapses. NMJ defects are first detectable at postnatal day 5 (P5), including presynaptic defects of terminal arborization and intermediate neurofilament aggregation in MNs, poor postsynaptic organization of AChRs in muscle, as well as reduced synaptic vesicle density and release at the NMJ (7-9). Importantly, similar NMJ defects have been reported in type I (the most severe type) SMA human fetuses (10). SMA MNs have also been shown to be hyperexcitable and loss of proprioceptive synapses on the somata, and proximal dendrites of SMA MNs (MN deafferentation) occurs no later than P4 (11-13). These findings indicate that both peripheral (NMJs) and central (sensory-motor) synapses are affected in SMA mice at early stage of disease. Although SMA is clinically manifested primarily in MNs, recent studies have shown that other cell types and nonneuronal tissues are also involved (13,14,15). SMN,...

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confidence: 84%

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Zhang

Pinto

Wan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

161

140

View full text Add to dashboard Cite

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“…In addition, reduced neurotransmitter release and decreased numbers of docked vesicles that precede axonal degeneration and/or motor neuron death have been reported at synapses of severe SMA mouse models (28,29). Notably, accumulation of synaptic vesicles (SVs) away from release sites was observed in SMA fetal samples (30). The proximate cause of these synaptic changes is unclear.…”

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confidence: 99%

“…The proximate cause of these synaptic changes is unclear. Numerous hypotheses have been proposed, including functional abnormalities in axonal transport and/or calcium channel loss in the nerve terminals (25)(26)(27)(28)(29)(30), but none have explained the defects observed in SMA presynaptic regions.…”

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confidence: 99%

Decreased function of survival motor neuron protein impairs endocytic pathways

Dimitriadi

Derdowski

Kalloo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.endocytic trafficking | survival motor neuron | spinal muscular atrophy | C. elegans | infection S pinal muscular atrophy (SMA) is one of the most severe neuromuscular diseases of childhood, with an incidence of 1 in 10,000 live births and a high carrier frequency of roughly 1 in 40 Caucasians (1-3). SMA is caused by reduced levels of the ubiquitously expressed survival of motor neuron (SMN) protein and results in degeneration of α-spinal cord motor neurons, muscle weakness, and/or death. Two human genes encode the SMN protein, SMN1 and SMN2. SMA alleles arise at relatively high frequency due to small intrachromosomal de novo rearrangements including the SMN1 locus (4). Patients often carry homozygous SMN1 deletions, although missense and nonsense alleles exist (5). Multiple copies of SMN2 rarely compensate for loss of SMN1 due to a C > T nucleotide change in SMN2 exon 7 that perturbs pre-mRNA splicing and results in a truncated protein of diminished function and stability (SMNΔ7) (5-9).SMN has numerous roles and interacts with various proteins, yet it remains unclear which interactions are most pertinent to SMA pathogenesis. As a component of the Gemin complex, SMN is required for biogenesis of small nuclear ribonucleoprotein (snRNP) particles critical for pre-mRNA splicing (10-12). Furthermore, SMN is needed for stress granule formation (13,14), is found in RNP granules moving through neuronal processes, and is part of RNP complexes implicated in synaptic local translation (15)(16)(17)(18)(19)(20). Additional roles for SMN, in transcription (21), in the PTEN-mediated protein synthesis pathway (22), in translational control (23), and in cell proliferation/differentiation (24), have been described. Importantly, no consensus has been reached regarding the cellular and molecular pathways wh...

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“…1). These observations, initially made in SMA mice, have now been confirmed in human patients and are suggestive of a disease that begins as a synaptopathy [20]. Although SMA is a predominantly neuromuscular disorder, the most severe form These include the heart, vasculature, pancreas, bone, and liver [21].…”

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confidence: 74%

Spinal Muscular Atrophy: Journeying From Bench to Bedside

2014

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Spinal muscular atrophy (SMA) is a frequently fatal neuromuscular disorder and the most common inherited cause of infant mortality. SMA results from reduced levels of the survival of motor neuron (SMN) protein. Although the disease was first described more than a century ago, a precise understanding of its genetics was not obtained until the SMA genes were cloned in 1995. This was followed in rapid succession by experiments that assigned a role to the SMN protein in the proper splicing of genes, novel animal models of the disease, and the eventual use of the models in the pre clinical development of rational therapies for SMA. These successes have led the scientific and clinical communities to the cusp of what are expected to be the first truly promising treatments for the human disorder. Yet, important questions remain, not the least of which is how SMN paucity triggers a predominantly neuromuscular phenotype. Here we review how our understanding of the disease has evolved since the SMA genes were identified. We begin with a brief description of the genetics of SMA and the proposed roles of the SMN protein. We follow with an examination of how the genetics of the disease was exploited to develop genetically faithful animal models, and highlight the insights gained from their analysis. We end with a discussion of ongoing debates, future challenges, and the most promising treatments to have emerged from our current knowledge of the disease.

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Synaptic defects in type I spinal muscular atrophy in human development

Cited by 78 publications

References 52 publications

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Decreased function of survival motor neuron protein impairs endocytic pathways

Spinal Muscular Atrophy: Journeying From Bench to Bedside

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