Early loss of axons limits the therapeutic window in a mouse model of spinal muscular atrophy.
5 affiliations
- 1Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, EH8 9XD, UK.
- 2Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK.
- 3Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, EH8 9XD, UK. [email protected].
- 4Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK. [email protected].
- 5College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. [email protected].
Abstract
Current treatments for spinal muscular atrophy have significantly improved patient prognosis, but still fall short of a full cure, particularly when administered after symptom onset. To improve future therapies, it is essential to identify the early pathological events that currently limit treatment efficacy. Here we have investigated the vulnerability and maturation of intramuscular motor axons in the SmnΔ7 mouse model of spinal muscular atrophy using a panel of cranial muscles with differing susceptibility to disease. We demonstrate that although there is intermuscular heterogeneity in neuromuscular junction pathology, they are united by a common loss of motor axons. We show that the timing of motor axon loss differs between muscles, but that motor axon loss precedes structural denervation and can occur by postnatal day 1 in highly vulnerable muscles. Electron microscopy of intramuscular axons revealed that axonal maturation and myelination are grossly normal prior to subsequent postnatal degeneration. We note that axons lack the traditional morphological correlates of axon degeneration but can be visualised using antibodies which detect degenerating neurofilaments. Treatment with SMN-upregulating therapy SMN-C8 at best preserves intramuscular axons when administered before the onset of degeneration but is unable to reverse damage or promote regeneration once axon loss has occurred. Collectively this data demonstrates that SMN-upregulating therapy can prevent motor axon loss, but the capacity is limited by the number of intramuscular axons which remain at the time of treatment onset. This work highlights the importance of developing complementary therapies which can promote motor axon regeneration to act in synergy with SMN-upregulating compounds.
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BibTeX
@article{comley2026early,
title = {{Early loss of axons limits the therapeutic window in a mouse model of spinal muscular atrophy.}},
author = {Laura H Comley and Inga Partlova and Charles Nyasa and A'ishah Shaikh and Lyndsay M Murray},
journal = {BMC neuroscience},
year = {2026},
month = aug,
doi = {10.1186/s12868-026-01034-1},
url = {https://europepmc.org/article/MED/42972236},
note = {CC BY},
}
RIS
TY - JOUR
TI - Early loss of axons limits the therapeutic window in a mouse model of spinal muscular atrophy.
AU - Laura H Comley
AU - Inga Partlova
AU - Charles Nyasa
AU - A'ishah Shaikh
AU - Lyndsay M Murray
PY - 2026
DA - 2026/08/06
JO - BMC neuroscience
DO - 10.1186/s12868-026-01034-1
UR - https://europepmc.org/article/MED/42972236
AB - Current treatments for spinal muscular atrophy have significantly improved patient prognosis, but still fall short of a full cure, particularly when administered after symptom onset. To improve future therapies, it is essential to identify the early pathological events that currently limit treatment efficacy. Here we have investigated the vulnerability and maturation of intramuscular motor axons in the SmnΔ7 mouse model of spinal muscular atrophy using a panel of cranial muscles with differing susceptibility to disease. We demonstrate that although there is intermuscular heterogeneity in neuromuscular junction pathology, they are united by a common loss of motor axons. We show that the timing of motor axon loss differs between muscles, but that motor axon loss precedes structural denervation and can occur by postnatal day 1 in highly vulnerable muscles. Electron microscopy of intramuscular axons revealed that axonal maturation and myelination are grossly normal prior to subsequent postnatal degeneration. We note that axons lack the traditional morphological correlates of axon degeneration but can be visualised using antibodies which detect degenerating neurofilaments. Treatment with SMN-upregulating therapy SMN-C8 at best preserves intramuscular axons when administered before the onset of degeneration but is unable to reverse damage or promote regeneration once axon loss has occurred. Collectively this data demonstrates that SMN-upregulating therapy can prevent motor axon loss, but the capacity is limited by the number of intramuscular axons which remain at the time of treatment onset. This work highlights the importance of developing complementary therapies which can promote motor axon regeneration to act in synergy with SMN-upregulating compounds.
SN - 1471-2202
ER -