Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease.
Apoptosis is a hallmark of motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) [1]. In a widely used mouse model of motoneuron disease (progressive motor neuronopathy or pmn) [2-4], transgenic expression of the anti-apoptotic bcl-2 gene [5] or treatment with glial cell-derived neurotrophic factor [6] prevents the apoptosis of the motoneuron soma; however, they were unable to affect the life span of the animals. The goal of the present work was to determine whether the pmn phenotype could be rescued by means of a gene that inhibits axon degeneration. For this reason, the pmn mice were crossed with mice bearing the dominant Wlds ("slow Wallerian degeneration") mutation, which slows axon degeneration and synapse loss [7-9]. We show here that the Wlds gene product attenuates symptoms, extends life span, prevents axon degeneration, rescues motoneuron number and size, and delays retrograde transport deficits in pmn/pmn mice. These results suggest new pathogenic mechanisms and therapeutic avenues for motoneuron diseases.
Ferri
Anna
A
Department of APSIC, Division of Pharmacology, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
Sanes
Joshua R
JR
Coleman
Michael P
MP
Cunningham
Jeanette M
JM
Kato
Ann C
AC
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001369:Axons / Q000473:pathology*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000627:therapeutic use; D009469:Neuromuscular Junction / Q000033:anatomy & histology; D013194:Staining and Labeling; D013569:Synapses / Q000473:pathology*
D009419:Nerve Tissue Proteins; C442580:Wld protein, mouse