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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    • "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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    • "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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