Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) leads to paralysis from the death of motor neurons in the spinal cord and brainstem. It is incurable, and patients typically die within three to five years of disease onset. Neurodegenerative diseases like ALS can progress slowly, with years of clinically undetectable symptoms followed by rapid deterioration. Although ALS selectively targets motor neurons, it has remained unclear whether particular synapses are selectively targeted and whether these synapses are lost gradually or abruptly.

In an article in this issue (page 408), Pico Caroni and colleagues addressed this issue by creating a quantitative map of the innervation of hindlimb muscle compartments by motor neurons in the mouse. They then went on to study the mechanisms of early disease progression in a mouse model of ALS.

Motor neurons innervating skeletal muscle fibers are subdivided into three functional subtypes—fast twitch and fast fatiguable (FF), fast twitch and fatigue resistant (FR) and slow twitch (S). The authors used transgenic mice expressing green fluorescent protein in only a few neurons and mapped the distribution of all synapses made by individual motor neurons in the lateral gastrocnemius muscle. Once they created a topographic map of motor neuron innervation, they analyzed denervation patterns in mice containing a mutation in the enzyme superoxide dismutase (SOD1). In this familial ALS mouse model, they found that FF axons were selectively affected early on in the disease and that these abruptly disconnected from their peripheral synapses when the mice were 48–52 days old. FR motor neurons innervating the same muscle compartments compensated initially for this loss by reinnervating neuromuscular junctions (NMJs) on the muscle fibers, but over time, were less able to maintain the additional NMJs. They then started pruning their nerve branches by the time the mice were 80–90 days old. S-type motor neurons were particularly resistant to disease, and maintained expanded motor units up to the time the mice died.

What makes the FF and FR motor neuron axons selectively vulnerable to disease? The authors did cross-innervation experiments and nerve crush studies and concluded that the early vulnerability of FF motor neurons xreflects a vulnerability of the presynaptic motor neuron axon rather than its target muscle or peripheral synapses. They also found that axonal transport was particularly vulnerable in FF and to a lesser degree in FR axons, leading to synaptic vesicle stalling and loss from NMJs. In the figure, the NMJ in the center has lost all synaptic signal (green, synaptic vesicle marker SV2; red, acetylcholine receptor) but is still innervated. Other NMJs may be less affected, like the lower one in the figure. Daily applications of the growth factor ciliary neurotrophic factor (CNTF) protected FF axons from synaptic vesicle loss and peripheral pruning and also helped to maintain the expanded size and innervation of compensating FR motor neuron axons. CNTF helped to boost axonal resistance to disease by causing neurofilament density reductions in both FF and FR neurons and by preventing the upregulation of an anti-apoptotic protein, Bc12a1-a, in motor neurons.

By providing a quantitative account of the selective vulnerability of different motor neuron populations during the progression of disease, this work opens up new possibilities for treating ALS and related motor neuron disorders.