Pun, S, Santos, AF, Saxena, S, Xu, L and Caroni, P. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9: 408-419

Friedrich Miescher Institut, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Nature Neuroscience (Impact Factor: 16.1). 04/2006; 9(3):408-19. DOI: 10.1038/nn1653
Source: PubMed


Neurodegenerative diseases can have long preclinical phases and insidious progression patterns, but the mechanisms of disease progression are poorly understood. Because quantitative accounts of neuronal circuitry affected by disease have been lacking, it has remained unclear whether disease progression reflects processes of stochastic loss or temporally defined selective vulnerabilities of distinct synapses or axons. Here we derive a quantitative topographic map of muscle innervation in the hindlimb. We show that in two mouse models of motoneuron disease (G93A SOD1 and G85R SOD1), axons of fast-fatiguable motoneurons are affected synchronously, long before symptoms appear. Fast-fatigue-resistant motoneuron axons are affected at symptom-onset, whereas axons of slow motoneurons are resistant. Axonal vulnerability leads to synaptic vesicle stalling and accumulation of BC12a1-a, an anti-apoptotic protein. It is alleviated by ciliary neurotrophic factor and triggers proteasome-dependent pruning of peripheral axon branches. Thus, motoneuron disease involves predictable, selective vulnerability patterns by physiological subtypes of axons, episodes of abrupt pruning in the target region and compensation by resistant axons.

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Available from: Smita Saxena, Apr 01, 2015
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    • "to remodel and make new junctions through collateral branching, and previous studies in mouse models of familial ALS have demonstrated that subtypes of motor neurons demonstrate compensatory plasticity (Frey et al., 2000; Schaefer et al., 2005; Pun et al., 2006). Our investigations suggest that this compensatory plasticity might be occurring in the neurons that are potentially resistant to excitotoxicity. "
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    ABSTRACT: There is a desperate need for targeted therapeutic interventions that slow the progression of amyotrophic lateral sclerosis (ALS). ALS is a disorder with heterogeneous onset, which then leads to common final pathways involving multiple neuronal compartments that span both the central and peripheral nervous system. It is believed that excitotoxic mechanisms might play an important role in motor neuron death in ALS. However, little is known about the mechanisms by which excitotoxicity might lead to the neuromuscular junction degeneration that characterizes ALS, or about the site at which this excitotoxic cascade is initiated. Using a novel compartmentalised model of site-specific excitotoxin exposure in lower motor neurons in vitro, we found that spinal motor neurons are vulnerable to somatodendritic, but not axonal, excitotoxin exposure. Thus, we developed a model of somatodendritic excitotoxicity in vivo using osmotic mini pumps in Thy-1-YFP mice. We demonstrated that in vivo cell body excitotoxin exposure leads to significant motor neuron death and neuromuscular junction (NMJ) retraction. Using confocal real-time live imaging of the gastrocnemius muscle, we found that NMJ remodelling preceded excitotoxin-induced NMJ degeneration. These findings suggest that excitotoxicity in the spinal cord of individuals with ALS might result in a die-forward mechanism of motor neuron death from the cell body outward, leading to initial distal plasticity, followed by subsequent pathology and degeneration. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Mar 2015 · Disease Models and Mechanisms
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    • "In some models of motor neuron disease, motor neurons are thought to die through a dying-back degeneration process (Fischer et al., 2004; Pun et al., 2006). This phenomenon is initiated by a dysfunction of the axonal periphery, "
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    ABSTRACT: Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Full-text · Article · Feb 2015 · Brain
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    • "For example, imposing moderate levels of activity in mouse models of amyotrophic lateral sclerosis (ALS) delays onset and slow progression of disease signs, reducing premature mortality (Kirkinezos et al., 2003; Veldink et al., 2003; Liebetanz et al., 2004; Deforges et al., 2009; Gordon et al., 2010; de Almeida et al., 2012). By contrast, intensive activity has also been reported to accelerate disease progression, both in mouse models and in sporadic forms of human ALS, perhaps through excitotoxicity or enhancing vulnerability to reactive oxygen species (Carri et al., 2003; Bruijn et al., 2004; Carrasco et al., 2004; Mahoney et al., 2004; Al-Chalabi & Leigh, 2005; Chio et al., 2005; Boillee et al., 2006; Pun et al., 2006; David et al., 2007; Bell & Hardingham, 2011; Alvarez et al., 2013; Mehta et al., 2013). "
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    ABSTRACT: Activity and disuse of synapses are thought to influence progression of several neurodegenerative diseases in which synaptic degeneration is an early sign. Here we tested whether stimulation or disuse renders neuromuscular synapses more or less vulnerable to degeneration, using axotomy as a robust trigger. We took advantage of the slow synaptic degeneration phenotype of axotomised neuromuscular junctions in flexor digitorum brevis (FDB) and deep lumbrical (DL) muscles of WldS mutant mice. First, we maintained ex vivo FDB and DL nerve-muscle explants at 320C for up to 48 hours. About 90% of fibres from WldS mice remained innervated, compared with about 36% in wild-type muscles at the 24 h checkpoint. Periodic high frequency nerve stimulation (100Hz: 1 s/100s) reduced synaptic protection in WldS preparations by about 50%. This effect was abolished in reduced Ca2+ solutions. Next, we assayed FDB and DL innervation after 7 days of complete tetrodotoxin (TTX)-block of sciatic nerve conduction in vivo, followed by tibial nerve axotomy. Five days later, only about 9% of motor endplates remained innervated in the paralysed muscles, compared with about 50% in 5d-axotomised muscles from saline-control treated WldS mice with no conditioning nerve block. Finally, we gave mice access to running wheels for up to four weeks prior to axotomy. Surprisingly, exercising WldS mice ad libitum for four weeks increased about two-fold the amount of subsequent axotomy-induced synaptic degeneration. Together, the data suggest that vulnerability of mature neuromuscular synapses to axotomy, a potent neurodegenerative trigger, may be enhanced bimodally, either by disuse or by hyperactivity.
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