Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes

Abstract

Summary: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in axonal transport have been identified in several ALS models, but in vivo evidence remains limited, thus their pathogenetic importance remains to be fully resolved. We therefore analyzed the in vivo dynamics of retrogradely transported, neurotrophin-containing signaling endosomes in nerve axons of two ALS mouse models with mutations in the RNA processing genes TARDBP and FUS. TDP-43M337V mice, which show neuromuscular pathology without motor neuron loss, display axonal transport perturbations manifesting between 1.5 and 3 months and preceding symptom onset. Contrastingly, despite 20% motor neuron loss, transport remained largely unaffected in FusΔ14/+ mice. Deficiencies in retrograde axonal transport of signaling endosomes are therefore not shared by all ALS-linked genes, indicating that there are mechanistic distinctions in the pathogenesis of ALS caused by mutations in different RNA processing genes. : Sleigh et al. address the importance of disturbances in axonal transport in two mouse models for ALS. They find that deficiencies in the in vivo axonal delivery of target tissue-derived survival factors are not a common feature of all ALS mouse models, suggesting mechanistic distinctions in different ALS-linked genes. Keywords: amyotrophic lateral sclerosis, ALS, intravital imaging, motor neuron disease, MND, RNA-binding protein, TARDBP