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<jats:title>Abstract</jats:title><jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in the basic neuronal process of axonal transport have been identified in several ALS models. However, <jats:italic>in vivo</jats:italic> evidence of early/pre-symptomatic deficiencies in neuronal cargo trafficking remains limited, thus the pathogenic importance of axonal transport to the ALS disease spectrum remains to be fully resolved. We therefore analysed the <jats:italic>in vivo</jats:italic> dynamics of retrogradely transported, neurotrophin-containing signalling endosomes in motor neuron axons of two new mouse models of ALS that have mutations in different RNA processing genes (<jats:italic>Tardbp</jats:italic> and <jats:italic>Fus</jats:italic>). TDP-43<jats:sup>M337V</jats:sup> mice, which show neuromuscular pathology but no overt motor neuron loss, displayed <jats:italic>in vivo</jats:italic> perturbations in axonal transport that manifested between 1.5 and 3 months and preceded motor symptom onset. In contrast, signalling endosome transport remained largely unaffected in mutant Fus<jats:sup>Δ14/+</jats:sup> mice, despite 20% motor neuron loss. These findings indicate that deficiencies in retrograde neurotrophin signalling and axonal transport are not common to all ALS-linked genes, and that there are inherent and mechanistic distinctions in the pathogenesis of ALS caused by mutations in different RNA processing genes.</jats:p>

Original publication

DOI

10.1101/438812

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

09/10/2018