Journal
CELL REPORTS
Volume 30, Issue 11, Pages 3655-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.02.078
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Funding
- Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship [103191/Z/13/Z]
- Medical Research Council Career Development Award [MR/S006990/1]
- Motor Neurone Disease Association
- Medical Research Council
- American Amyotrophic Lateral Sclerosis Association
- Rosetrees Trust
- Wellcome Trust Senior Investigator Award [107116/Z/15/Z]
- European Union's Horizon 2020 Research and Innovation Programme [739572]
- UK Dementia Research Institute Foundation
- Wellcome Trust [107116/Z/15/Z, 103191/Z/13/Z] Funding Source: Wellcome Trust
- MRC [MR/S006508/1, MR/M008606/1, UKDRI-1005, MR/S006990/1] Funding Source: UKRI
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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-43(M337V) 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 Fus(Delta 14/+) 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.
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