Research from QS Motor Neuron Disease Centre identifies a new key deficit in Motor Neuron Disease

"In ALS/MND, the fast motor neurons, which perform precise movements like hand control, are the most vulnerable and first to become affected. In contrast, slow motor neurons that are involved in maintaining posture are more resistant to ALS/MND. We report that fast motor neurons in ALS mice display deficits in axonal transport whereas slow motor neurons remain unperturbed." Prof Giampietro Schiavo, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology

A currently unexplained phenomenon in amyotrophic lateral sclerosis (ALS) is that fast motor neurons are preferentially vulnerable to disease whereas slow motor neurons are generally more resistant. This has also been observed in different mouse models of the disease, which provide an opportunity to better understand this selectivity.

Researchers at Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, investigated the influences of Brain Derived Neurotrophic Factor (BDNF) and motor neuron subtype on in vivo axonal transport in healthy and ALS mice. BDNF is a key survival protein for neurons that is recognised at axon terminals, where it is taken up and packaged into specialised organelles called signalling endosomes for long-range delivery along axons to neuronal cell bodies.

"We have previously developed an in vivo imaging technique that allows us to assess axonal transport, which is a process that ensures the bi-directional delivery of cargoes between neuron cell bodies and the tips of axons. Using this method, we revealed that stimulation of healthy motor neuron terminals with the neurotrophic factor BDNF increases axonal signalling endosome speeds in fast, but not slow, motor neurons. However, in addition to their axonal transport deficits, fast motor neurons in ALS mice are refractory to BDNF stimulation, likely contributing to their preferential vulnerability in disease. Together, these findings indicate that BDNF signalling is impaired in ALS/MND mice." Dr Andrew Tosolini, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology

In healthy mice, BDNF stimulation of muscle enhanced the speed of signalling endosome axonal transport in fast, but not slow, α-Motor Neurons (MNs), revealing a previously unappreciated physiological distinction in the α-MN subtypes. In disease, baseline axonal transport deficits were observed in fast motor neurons alone, which also displayed insensitivity to BDNF, suggesting a possible cause for the dysfunctional trafficking in ALS. 

"This work highlights an important difference in the response of ALS/MND motor neurons to BDNF, both in adult and embryonic mice, emphasising the value of combining in vivo and in vitro models of disease. The study also complements our recent work investigating GDNF, providing further evidence of altered neurotrophic factor signalling in ALS/MND". Dr Ellie Rhymes, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology

This research project reveals that cell- and non-cell autonomous BDNF signalling is impaired in ALS mouse motor neurons, and thus identifies a new key deficit in ALS.

"This work corroborates that not all motor neurons are equally affected by ALS/MND, and highlights the great need for more focus on neuronal selectivity in this and other neurological diseases. We expect that further investigations into the fundamental biological differences between neuronal subtypes will reveal clues as to what causes some motor neurons to be susceptible to ALS/MND and others to be relatively unaffected. With this knowledge, we hope to better design effective therapies for ALS/MND patients". Dr James Sleigh, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology

Links

• Tosolini, A.P., Sleigh, J.N., Surana, S. et al. (2022) BDNF-dependent modulation of axonal transport is selectively impaired in ALS. acta neuropathol commun 10, 121 (2022). https://doi.org/10.1186/s40478-022-01418-4
• MND Association Research     blog
• Professor Schiavo's academic profile
• Dr Andrew Tosolini’s academic profile
• Dr Ellie Rhymes' academic profile
• Dr James Sleigh's academic profile
• Dr Sunaina Surana’s academic profile

Images:

• Axonal transport of fluorescently-labelled signalling endosomes in intact axons found in the sciatic nerve of a live, anesthetised mouse.
• Schematic summarising the key findings from the study.