SMN Requirement for Synaptic Vesicle, Active Zone and Microtubule Postnatal Organization in Motor Nerve Terminals

Torres-Benito, Laura; Neher, Margret Feodora Maria; Cano, Raquel; Ruiz, Rocío; Tabares, Lucı́a

doi:10.1371/journal.pone.0026164

Cited by 79 publications

(79 citation statements)

References 72 publications

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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).…”

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confidence: 99%

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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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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.…”

mentioning

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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“…This allows for the accurate assessment of developmental and degenerative neuromuscular phenotypes, including those outlined here and others - for example, terminal and nodal sprouting (Murray et al, 2010b), paralysis-induced remodeling (Murray et al, 2008a), neurofilament accumulation/axonal swelling (Ling et al, 2012; Valdez et al, 2010), terminal Schwann cell number, morphology, and sprouting (Murray et al, 2012), active zone density (Chen et al, 2012), active zone association with synaptic vesicles (Torres-Benito et al, 2011), mitochondrial density and microtubule maturity (Torres-Benito et al, 2011), intramuscular axon numbers (Murray et al, 2010b), and AChR subunit-switching (Kong et al, 2009). We have used a mouse model of the peripheral neuropathy Charcot-Marie-Tooth disease type 2D ( Gars Nmf249 /+ ) to demonstrate the utility of the lumbrical muscle preparation for highlighting pathological NMJ phenotypes.…”

Section: Resultsmentioning

confidence: 99%

Morphological analysis of neuromuscular junction development and degeneration in rodent lumbrical muscles

Sleigh

Burgess

Gillingwater

et al. 2014

Journal of Neuroscience Methods

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Background The neuromuscular junction (NMJ) is a specialised synapse formed between a lower motor neuron and a skeletal muscle fibre, and is an early pathological target in numerous nervous system disorders, including amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), and spinal muscular atrophy (SMA). Being able to accurately visualize and quantitatively characterise the NMJ in rodent models of neurological conditions, particularly during the early stages of disease, is thus of clear importance. New Method We present a method for dissection of rodent deep lumbrical muscles located in the hind-paw, and describe how to perform immunofluorescent morphological analysis of their NMJs. Results These techniques allow the temporal assessment of a number of developmental and pathological NMJ phenotypes in lumbrical muscles. Comparison with Existing Methods Small muscles, such as the distal hind-limb lumbrical muscles, possess a major advantage over larger muscles, such as gastrocnemius, in that they can be whole-mounted and the entire innervation pattern visualised. This reduces preparation time and ambiguity when evaluating important neuromuscular phenotypes. Conclusions Together, these methods will allow the reader to perform a detailed and accurate analysis of the neuromuscular system in rodent models of disease in order to identify pertinent features of neuropathology.

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“…Although autophagy and other degeneration features were not prominent, changes such as a lack of NFs, decreased densities of synaptic vesicles, and accumulation of multilamellar bodies suggest that pathologic alterations and physiologic deficits developed in the NMJ in association with the development of the proximal NFfilled swellings that characterize IDPN axonopathy before overt degeneration. Neurofilaments have been shown to coorganize with synaptic vesicle clusters in terminals, and this relationship is altered in the mutated survival motor neuron mouse model (41). It is thus possible that NF alterations modify synaptic vesicle dynamics and that this contributes to altered neurotransmission and perhaps to final terminal retraction.…”

Section: Discussionmentioning

confidence: 99%

Chronic Proximal Axonopathy in Rats is Associated With Long-Standing Neurofilament Depletion in Neuromuscular Junctions and Behavioral Deficits

Soler-Martín

Boadas-Vaello

Verdú

et al. 2014

J Neuropathol Exp Neurol

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In rodents exposed to 3,3'-iminodipropionitrile (IDPN), neurofilaments (NFs) accumulate in swollen proximal axon segments; this also occurs in motor neurons of patients with amyotrophic lateral sclerosis. We hypothesized that early loss of NFs in neuromuscular junctions (NMJs) in IDPN proximal neuropathy would result in neuromuscular dysfunction and lead to neuromuscular detachment. Adult male rats were given 0 or 15 mmol/L IDPN in drinking water for up to 1 year. The IDPN-exposed rats dragged their tails and had impaired endurance in a grip test. Neuromuscular junctions and distal axons were examined in the levator auris longus muscle after 3, 6, 9, and 12 months. Neuromuscular junctions showed a progressive reduction in NF immunolabeling, which became undetectable in up to 70% of the NMJs after 12 months. Neurofilament labeling was also reduced in preterminal axons and in a more proximal axon level within the muscle. Triple-label analysis with antisyntaxin demonstrated that the terminals remained in place and usually contained a few minute NF bundles. Electron microscopy revealed the disappearance of terminal NFs, reduced content in synaptic vesicles, and accumulation of multilamellar bodies, but scant degeneration. Thus, IDPN proximal neurofilamentous axonopathy is associated with NF depletion in motor terminals; motor weakness and structural changes in the NMJs suggest impaired synaptic function despite long-term preservation of the NMJs.

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SMN Requirement for Synaptic Vesicle, Active Zone and Microtubule Postnatal Organization in Motor Nerve Terminals

Cited by 79 publications

References 72 publications

Decreased function of survival motor neuron protein impairs endocytic pathways

Decreased function of survival motor neuron protein impairs endocytic pathways

Morphological analysis of neuromuscular junction development and degeneration in rodent lumbrical muscles

Chronic Proximal Axonopathy in Rats is Associated With Long-Standing Neurofilament Depletion in Neuromuscular Junctions and Behavioral Deficits

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