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Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF

Abstract

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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Figure 1: Quantitative topographic map of the motor units innervating the LGC muscle in the mouse.
Figure 2: Analysis of subcompartment denervation patterns in hindlimb muscles of G93A SOD1 mice reveals grouping into three distinct classes.
Figure 3: Identification of motoneuron subtypes vulnerable and resistant to axon pruning in G93A SOD1mice.
Figure 4: Selective vulnerability of FF and FR motoneuron axons in G93A SOD1 mice.
Figure 5: Early stalling and loss of synaptic vesicles from intramuscular axons and NMJs in motoneuron disease.
Figure 6: Closely comparable patterns of selective FF and FR axon pruning in two FALS models with distinct disease onset times.
Figure 7: Local applications of CNTF alleviate FALS-associated axonal vulnerability.
Figure 8: CNTF-sensitive axonal vulnerability is followed by lactacystin-sensitive peripheral axon pruning.

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Acknowledgements

We are grateful to C. Schneider (Friedrich Miescher Institut) for technical assistance, S. Lefler (Friedrich Miescher Institut) for myosin heavy chain (MHC) labeling data, M.T. Carri (University of Rome, Tor Vergata, Italy) for sharing with us their results on Bc12a1-a induction in FALS and S. Arber (Friedrich Miescher Institut and Biozentrum, University of Basel) for comments on the manuscript. S.S. was supported by EU FP6 (NeuroNE). The Friedrich Miescher Institut is part of the Novartis Research Foundation.

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Pun, S., Santos, A., Saxena, S. et al. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9, 408–419 (2006). https://doi.org/10.1038/nn1653

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