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.

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

“…Indeed, our electrophysiological data demonstrate improved motor recovery in CNTFinjected mice, which is in agreement with previous studies describing its role in stimulation of motoneuron regeneration in vitro and in vivo. 30,31 Intrasciatic administration of AAV8 provides a useful tool for specific Schwann cell transduction, compared with other viral vectors described so far. Through this route of administration, we did not observe the neuronal tropism described for this AAV serotype after intracranial injection in the CNS, through intrathecal or intramuscular administration.…”

The phenotypic variability of amyotrophic lateral sclerosis

“…101 The molecular and cellular biology underlying the pheno typic variation remain elusive. Motor neurons seem strikingly vulnerable to ALS, those with a large diameter more so than small ones, 102,103 whereas the oculomotor neurons and those in Onuf 's nucleus are far more resistant. Why ALS starts in spinal neurons in some patients, but in bulbar neurons in others, remains puzzling.…”

Sclérose latérale amyotrophique, jonction neuromusculaire et déficit énergétique

“…Le premier événement semble être la destruction de la jonction neuromusculaire, en particulier de la structure post-synaptique. La dégradation de l'axone du motoneurone puis la destruction du corps cellulaire surviennent ensuite [4][5][6]. Pendant très longtemps, il paraissait prometteur de trouver une stratégie thérapeutique qui permette de sauver le corps cellulaire du motoneurone de l'apoptose, ce qui préserverait les chances de régénération de la jonction neuromusculaire.…”