Expression of a Mutant SEMA3A Protein with Diminished Signalling Capacity Does Not Alter ALS-Related Motor Decline, or Confer Changes in NMJ Plasticity after BotoxA-Induced Paralysis of Male Gastrocnemic Muscle

Moloney, Elizabeth B.; Hobo, Barbara; Winter, Fred de; Verhaagen, Joost

doi:10.1371/journal.pone.0170314

Cited by 13 publications

(12 citation statements)

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“…Our results show that female fast-fatigable MUs (surface of the tibialis anterior; see Materials and Methods) are much more likely to form expansions in SOD1 G37R / YFP mice, resulting in a net increase in MU size in females but not in males. This result is consistent with previous findings on botulinum toxin-induced axonal sprouting (Moloney et al, 2017), where fast-fatigable motor axons were more likely to sprout in female mice. Interestingly, this increased dynamism is associated with an earlier onset of motor deficits and an exacerbated pathology in our female mice, as shown by the loss of grip strength and the neuromuscular and spinal cord histopathology.…”

Section: Discussionsupporting

confidence: 93%

“…This scenario could also explain why females tended to have higher global levels of NMJ denervation despite the similar amount of asynchronous NMJ losses between males and females. However, this scenario is not entirely consistent with the notion that female fast-fatigable motor axons are intrinsically more inclined to sprout (Moloney et al, 2017). Hence, additional studies aimed at manipulating MUs expansions levels in males and females are required to determine whether they represent an adaptive or a maladaptive response in female SOD1 G37R mice.…”

Section: Discussionmentioning

confidence: 88%

“…Interestingly though, a recent study identified that women with ALS were twice as likely of having antibodies against two NMJ components, agrin and LRP4 (Rivner et al, 2017). Furthermore, Moloney et al (2017) identified sex-specific differences in botulinum toxin-induced axonal sprouting in mice, with female mice notably exhibiting more sprouting from ALS-vulnerable fast-fatigable MUs. These recent findings raise the possibility that sex-specific differences may impact local NMJ dynamism in ALS, which could be an important factor to consider for therapeutic development.…”

Section: Introductionmentioning

confidence: 99%

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Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Martineau

Polo

Velde

et al. 2020

eNeuro

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Progressive loss of neuromuscular junctions (NMJs) is an early event in amyotrophic lateral sclerosis (ALS), preceding the global degeneration of motor axons and being accompanied by new axonal sprouting within the same axonal arbor. Some aspects of ALS onset and progression seem to be affected by sex in animal models of the disease. However, whether there are sex-specific differences in the pattern or time course of NMJ loss and repair within single motor axons remains unknown. We performed further analysis of a previously published in vivo dataset, obtained from male and female SOD1 G37R mice. We found that NMJ losses are as frequent in male and female motor axons but, intriguingly, axonal sprouting is more frequent in female than male mice, resulting in a net increase of axonal arborization. Interestingly, these numerous new axonal branches in female mice are associated with a slightly faster decline in grip strength, increased NMJ denervation, and reduced a-motor neuron survival. Collectively, these results suggest that excessive axonal sprouting and motorunit (MU) expansion in female SOD1 G37R mice are maladaptive during ALS progression.Sex-specific differences in amyotrophic lateral sclerosis (ALS) progression have been identified in patients and in some animal models of the disease. However, the physio-pathologic changes underlying these disparities remain poorly defined. In this study, we identified that the pattern of motor axon retraction and regrowth in skeletal muscles is a novel factor to consider in our understanding of sex-linked differences in ALS. Analysis of single motor axons in a model of ALS identified that female motor axons were more likely to form compensatory branches, which was associated with a worse phenotype. These surprising findings highlight the necessity to more systematically evaluate the prevalence of sex-specific differences across animal models of ALS and in patients.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Martineau

Polo

Velde

et al. 2020

eNeuro

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“…The involvement of Sema3A in the pathogenesis of ALS has been suggested in a number of studies using ALS models in mice with some conflicting results 10 , 19 . Since many core biological processes and genetic elements are conserved between human and mouse, these findings in mice are considered suggestive.…”

Section: Discussionmentioning

confidence: 99%

ALS-related human cortical and motor neurons survival is differentially affected by Sema3A

et al. 2018

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by cell death of upper and lower motor neurons (MNs). The cause of MN cell loss is not completely understood but involves both cell autonomous and non-cell autonomous mechanisms. Numerous molecules have been implicated to be involved in the death of MNs. One such candidate is semaphorin 3A (Sema3A). In ALS patients, Sema3A was shown to be significantly upregulated in the motor cortex and downregulated in the spinal cord. In the mouse, Sema3A was shown to be an axon repellent molecule for MNs. Sema3A could also induce death of different neuronal types that are also repelled by it, including sensory, sympathetic, retinal, and cortical neurons. In contrast, astrocyte-specific knockout of Sema3A results in motor neuron cell death, consistent with the idea that Sema3A is a survival factor for mouse motor neurons. Here, we tested the response of human cortical neurons and spinal cord MNs to Sema3A. We found that Sema3A enhances the survival of spinal cord MNs. In contrast, Sema3A reduces the survival of cortical neurons. Thus, both upregulation of Sema3A in the cortex, or downregulation in the spinal cord of ALS patients is likely to directly contribute to MNs cell loss in ALS patients.

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“…Moreover, injecting specific antibodies against NRP1 or manipulating Sema3A expression using miR126-5p resulted in improvement in disease progression in vivo and in vitro (Venkova et al ., 2014; Maimon et al ., 2018). In contrast to these results, a recent study demonstrated that crossing mice expressing a truncated form of Sema3A with SOD1 G93A mice does not result in any rescue effect (Moloney et al ., 2017). An explanation for this contradiction could be the possibility that secreted factors such as Sema3A play a more complex role in the biology of MNs (Zahavi, Maimon and Perlson, 2017).…”

Section: Discussionmentioning

confidence: 75%

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

Maimon

Ankol

Weissova

et al. 2019

Preprint

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29Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease 30 with selective dysfunction; it causes the death of motor neurons (MNs). In spite of 31 some progress, currently no effective treatment is available for ALS. Before such 32 treatment can be developed, a more thorough understanding of ALS pathogenesis is 33 required. Recently, we demonstrated that ALS-mutated muscles contribute to ALS 34 pathology via secretion of destabilizing factors such as Sema3A; these factors trigger 35 axon degeneration and Neuromuscular Junction (NMJ) disruption. Here, we focus on 36 the molecular mechanism by which muscle contribute to MNs loss in ALS. We 37 identified CRMP4 as part of a retrograde death signal generated in response to 38 muscle-secreted Sema3A, in ALS-diseased MNs. Exposing distal axons to Sema3A 39 induces CRMP4-dynein complex formation and MN loss in both mouse (SOD1 G93A ) 40 and human-derived (C9orf72) ALS models. Introducing peptides that interfere with 41 CRMP4-dynein interaction in MN axons profoundly reduces Sema3A-dependent MN 42 loss. Thus, we discovered a novel retrograde death signal mechanism underlying MN 43 loss in ALS. 44 45 46 Summary 47 Maimon et al. identify a novel retrograde death mechanism that contribute to MN loss 48 in ALS, in which CRMP4-Dynein complex is form and retrogradely move along the 49 axon.50 51 52 53 105 Strittmatter, 2007). The canonical signaling events of CRMPs during Semaphorin 106 signaling involve their phosphorylation via GTPase activity, which further leads to 107 microtubule destabilization and axon retraction (Sasaki et al., 2002; Yamashita and 108 5 Goshima , 2012; Balastik et al., 2015). In addition to their role in mediating Sema3A 109 intrinsic responses, CRMPs were also reported to bind dynein and kinesin, and 110 modulate their function (Arimura et al., 2009; Rahajeng et al., 2010). Several studies 111 further demonstrated the involvement of CRMPs in neurodegenerative diseases 112 (Charrier et al., 2003; Yamashita and Goshima, 2012; Nagai, Baba and Ohshima, 113 2017). Specifically, CRMP4 expression levels were previously found to be elevated in 114 the SOD1 G93A mouse spinal cord, and were suggested to hamper MN health (Duplan 115 et al., 2010; Valdez et al., 2012; Nagai et al., 2015). However, the mechanism underline 116 the involvement of CRMP4 mediating cell death and its role in other ALS model is still 117 elusive. Moreover, mutations in CRMP4 were associated with ALS patients (Blasco et 118 al., 2013). 119 120 Here, we identified a novel retrograde death signal, triggered by Sema3A, which 121 facilitates MN loss in both murine and human ALS models. This process is mediated 122 by the formation of CRMP4-Dynein complex along diseased axons. Interfering with the 123 binding of CRMP4 to Dynein by using short blocking peptides rescues Sema3A-124 dependent MN loss in these ALS models. 125 126 Results 127 128 SOD G93A MNs and muscle co-cultures enhance MN loss 129 MN cell death is a key process in ALS pathology. Taking into consideratio...

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Expression of a Mutant SEMA3A Protein with Diminished Signalling Capacity Does Not Alter ALS-Related Motor Decline, or Confer Changes in NMJ Plasticity after BotoxA-Induced Paralysis of Male Gastrocnemic Muscle

Cited by 13 publications

References 73 publications

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

ALS-related human cortical and motor neurons survival is differentially affected by Sema3A

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

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