Increasing MuSK Activity Delays Denervation and Improves Motor Function in ALS Mice

María J Pérez-García,Steven J Burden

doi:10.1016/j.celrep.2012.08.004

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disease that progresses from detachment of motor nerve terminals to complete muscle paralysis and lethal respiratory failure within 5 years of diagnosis. Genetic studies have linked mutations in several genes to ALS, and mice bearing mutations in SOD1 recapitulate hallmark features of the disease. We investigated whether disease symptoms can be ameliorated by co-opting the retrograde signaling pathway that promotes attachment of nerve terminals to muscle. We crossed SOD1G93A mice with transgenic mice that express MuSK, a receptor tyrosine kinase that is required for retrograde signaling, and we used histological and behavioral assays to assess motor innervation and behavior. A 3-fold increase in MuSK expression delayed the onset and reduced the extent of muscle denervation, improving motor function for more than a month without altering survival. These findings suggest that increasing MuSK activity by pharmacological means has the potential to improve motor function in ALS.

Highlights

The withdrawal of motor axons from muscle is the first sign of disease in familial and sporadic forms of ALS, portending a progressive and devastating loss of motor function that culminates in lethal muscle paralysis within five years of diagnosis (Fischer et al, 2004; Pasinelli and Brown, 2006; Schaefer et al, 2005)
We wondered whether increasing MuSK expression in a mouse model of ALS would stabilize neuromuscular synapses, delay motor axon withdrawal, and increase muscle function
In SOD1G93A mice, denervation of the diaphragm muscle became evident at P120, and the extent of denervation increased gradually over the 20 days, reaching a maximum of ~50% at P140 (Figure 1), similar to the time course and extent of denervation observed in other muscles (Schaefer et al, 2005)

Summary

Introduction

The withdrawal of motor axons from muscle is the first sign of disease in familial and sporadic forms of ALS, portending a progressive and devastating loss of motor function that culminates in lethal muscle paralysis within five years of diagnosis (Fischer et al, 2004; Pasinelli and Brown, 2006; Schaefer et al, 2005). The mechanisms responsible for axon withdrawal are poorly understood, but the loss of neuromuscular synapses is sufficient to cause muscle paralysis and central to the disease. The subsequent loss of motor neurons has received more attention, preventing or delaying motor neuron cell death without preserving neuromuscular synapses cannot stop disease progression. The pathological hallmarks of the disease are well replicated in mice that overexpress mutant forms of SOD1 in motor

Results

Discussion

Conclusion