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

ARTICLES.com/natureneuroscienceSelective vulnerability and pruning of phasic

motoneuron axons in motoneuron disease alleviated

by CNTFSan Pun1,2, Alexandre Ferra~o Santos1,2, Smita Saxena1,2, Lan Xu1 & Pico Caroni1Neurodegenerative 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 pruningof 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.In neurodegenerative diseases, years of slowly progressing and clinically

undetectable alterations and losses set the stage for devastating clinical

phases when treatments produce disappointing results. Synapses are

lost early in disease but the mechanisms underlying this vulnerability

are not understood1. It is not clear whether particular synapses are lost

selectively, gradually or abruptly, and whether it is synapses, axons or

dendrites that are selectively targeted. The complexities of adult brain

circuitry pose formidable challenges to the elucidation of the mechanisms of early disease progression. However, in animal models of

motoneuron disease2,3, more accessible synapses between motoneurons

and muscles are also lost early on and in reproducible patterns4,5.

Motoneuron disease models thus provide uniquely advantageous

systems in which to investigate pathways of vulnerability and disease

progression in neurodegeneration. Such information is essential for

early detection and for the development of more effective treatments

against these diseases.Transgenic mice expressing human SOD1 point-mutant proteins

associated with familial amyotrophic lateral sclerosis (FALS; refs. 2,3)

develop paralytic motoneuron disease closely resembling human ALS.

The mechanism through which mutant SOD1 triggers disease seems to

involve pathogenic processes in the local environment of motoneurons6,7 and mitochondrial accumulation of...