In healthy mice, they found that BDNF enhanced the speed of transport in fast motor neurons but had no effect in slow motor neurons. When they repeated the test in ALS mice, they found that BDNF no longer had the same enhancing effect on the fast motor neurons.
First author Dr Andrew Tosolini, explained:
“We showed that in a healthy mouse, fast and slow motor neurons, which have different physiological properties, display similar axonal transport dynamics of signalling endosomes. Despite this, fast and slow motor neurons respond differently to BDNF stimulation as we observed an increase in the speeds of signalling endosomes but only in fast motor neurons. Contrary to its effects in the healthy mouse, we found that BDNF stimulation did not enhance the transport speeds of signalling endosomes in fast motor neurons in the ALS mouse, suggesting impairments in BDNF signalling in the vulnerable fast motor neurons. Collectively, these results indicate that some of the fine tuning in fast motor neurons are lost in ALS.”
The researchers then assessed the amount of BDNF in the muscles of healthy and ALS mice and found it was unaffected by disease. Instead, what they discovered was that the levels of BDNF receptors was altered in ALS animals, providing further evidence that BDNF signalling is dysregulated in ALS.
Study leader Prof. Giampietro Schiavo, Group Leader at the UK DRI at UCL, said:
“In ALS, the fast motor neurons, which perform precise movements like hand control, are the most vulnerable and first to become affected in disease. In contrast, slow motor neurons such as those involved in maintaining posture, are more resistant to ALS. Our results indicate that BDNF signalling is impaired in vulnerable motor neurons in ALS, which may help to explain why fast and slow motor neurons are affected differently by the disease. Our study represents a significant step forward in understanding the fundamental mechanisms involved in the disease, which in turn will enhance our ability to design better therapies for ALS.”
Next, the team plan to investigate how to restore BDNF signalling in vulnerable neurons in the ALS model, to see if this results in an amelioration of ALS symptoms. They also aim to confirm their results in different ALS model systems, including different ALS mouse models as well as in human iPSCs (induced pluripotent stem cells) to test whether the results can also be applied to human disease pathology.
To find out more about Prof Giampietro Schiavo's research, visit his UK DRI profile. To stay up to date on the latest research news and Institute updates, sign up to receive our monthly newsletter, ‘Inside Eye on UK DRI'.
Reference: Tosolini, A.P., Sleigh, J.N., Surana, S. et al. BDNF-dependent modulation of axonal transport is selectively impaired in ALS. acta neuropathol commun 10, 121 (2022). https://doi.org/10.1186/s40478...
Article published: 2 September 2022
Banner image credit: Dr Andrew Tosolini