A molecule has been created that might repair and restore brain and spinal cord function in mice with neurological disorders, it has been announced.
Scientists in the Medical Research Council Laboratory of Molecular Biology (MRC LMB), in Cambridge, UK, who worked with colleagues in Japan and Germany, say the synthetic "molecular bridge" allows novel interactions and opens the way to applications in neuronal circuit repair and remodelling.
Writing in Science, they say the design of the molecule means it can be extended to connect other cell types or could be used to remove connections in other disorders, such as epilepsy.
The molecule cerebellin-1 links neuronal cells with transmitters and receivers at synapses. Known as synaptic organisers, they are essential to help establish the vast communication network that underlies all nervous system functions.
The team examined if they could cut and paste structural elements from different organiser molecules to generate new ones with different binding properties. They produced CPTX, which was found to have an excellent ability to organise neuronal connections in cell cultures.
Dr Radu Aricescu, of the MRC Laboratory of Molecular Biology, said: "Damage in the brain or spinal cord often involves loss of neuronal connections in the first instance, which eventually leads to the death of neuronal cells.
“Prior to neuronal death, there is a window of opportunity when this process could be reversed in principle. We created a molecule that we believed would help repair or replace neuronal connections in a simple and efficient way.
“We were very much encouraged by how well it worked in cells and we started to look at mouse models of disease or injury where we see a loss of synapses and neuronal degeneration."
Following the successful cell culture experiments, the team tested their molecule’s effect in mice with cerebellar ataxia, by injecting the molecule into the mice’s brains before observing neuronal tissue repair and improved motor performance.
They went on to see if there would be similar effects in other mouse models of neuronal loss and degeneration, such as Alzheimer’s disease and spinal cord injury, and realised striking results in all animal models.
They recorded restored neuronal connections and improvements in memory, co-ordination and movement tests and saw the greatest impact in spinal cord injury, where motor function was restored for at least seven to eight weeks following a single injection into the site of injury.
The positive impact of injections in the brain lasted for about one week in the ataxia model, which has led them to continue improving it by looking to produce new and more stable versions of CPTX.
Dr Aricescu added: "There are many unknowns as to how synaptic organisers work in the brain and spinal cord, so we were very pleased with the results we saw.
“We demonstrate that we can restore neural connections that send and receive messages, but the same principle could be used to remove connections. The work opens the way to many applications in neuronal repair and remodelling: it is only imagination that limits the potential for these tools.”
Suzuki K, Elegheert J, Song I et al. A synthetic synaptic organizer protein restores glutamatergic neuronal circuits. Science 28 August 2020; doi: 10.1126/science.abb4853
https://science.sciencemag.org/content/369/6507/eabb4853/tab-article-info
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