Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

<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




Journal article


Cold Spring Harbor Laboratory

Publication Date