Neuregulin-1 Drives And Enables Spinal Cord Repair

A molecular signal, known as neuregulin-1, which drives and enables the spinal cord’s natural capacity for repair after injury, has been identified by researchers from King’s College London and the University of Oxford.

Every year more than 130,000 people suffer traumatic spinal cord injury (usually from a road traffic accident, fall or sporting injury) and related healthcare costs are among the highest of any medical condition – yet there is still no cure or adequate treatment.

These findings could one day lead to new treatments which enhance a spontaneous repair mechanism by manipulating the neuregulin-1 signal.

Spinal cord injury has devastating consequences for muscle and limb function, but the central nervous system does possess some limited capacity to repair itself naturally.

Understanding what drives this repair mechanism could aid the development of new treatment strategies aimed at boosting the self-healing capacity of the injured spinal cord by taking advantage of ‘tools’ that the spinal cord already possesses.

Neuregulin-1 and Spontaneous Remyelination

One of these tools, neuregulin-1, signals from the surface of damaged nerve fibres during a process called spontaneous remyelination.

Spontaneous remyelination is a period of natural regeneration that happens in the weeks following a spinal cord injury. The process takes place as a result of damage to spinal nerve fibres which have lost their insulating myelin sheath.

This myelin sheath is crucial for efficient communication between the brain and the body.

Axonal Nrg1

Axonal Nrg1 is required for Remak bundle structure and myelination in development and this is not compensated for over long periods of time. (A) Electron micrographs of sural nerves from 1-year-old Nrg1fl/fl control mice and Nrg1fl/fl;Nav1.8-Cre mice in which Nrg1 was ablated in a subpopulation of sensory neurons. The developmental phenotype characterized at 10 weeks of age (Fricker et al., 2009), of large unordered Remak bundles, within which axons are not separated by Schwann cell processes and which also contain axons with a diameter >1 µm (open triangle) persists at this age. Also singly sorted axons >1 µm in diameter and surrounded by a Schwann cell remain unmyelinated (asterisk). Scale bar = 2 µm. (B) G-ratio frequency distribution shows there is still a shift to larger G-ratios in the Nrg1fl/fl;Nav1.8-Cre mice, indicating a proportion of axons with thinner myelin sheaths (P < 0.001 Kolmogorov-Smirnov test) n = 3. (C) Counts of the number of unmyelinated axons in a 1:1 relationship with a Schwann cell and >1 µm in diameter as depicted in A by an asterisk, at both 10 weeks and 1 year of age. In summary there is no recovery in the developmental phenotype at 1 year of age, n = 3–4. Credit: Florence R. Fricker, et al. (2016), Brain.

However, this natural capacity for repair is not sufficient for full recovery and may account for the compromised function of surviving nerve fibres, which can affect balance, coordination and movement.

The researchers found that, in mice lacking the neuregulin-1 gene, spontaneous myelin repair was completely prevented and spinal nerve fibres remained demyelinated (i.e. unable to send nerve signals along the spinal cord).

They also discovered that mice without neuregulin-1 showed worse outcomes after spinal cord injury compared to mice with the gene intact, particularly in walking, balance and coordinated movements.

Molecular Switch

Not only did neuregulin-1 drive spontaneous remyelination, but it also served as a molecular switch for cells within the spinal cord to transform themselves into cells with remyelinating capacity.

This is unusual, according to the researchers, because the Schwann cells with new remyelinating capacity normally only myelinate nerve fibres in the peripheral nervous system – not the central nervous system, as observed here.

Elizabeth Bradbury, Professor of Regenerative Medicine & Neuroplasticity at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, and Medical Research Council Senior Fellow, said:

“Spinal cord injury could happen to anyone, at any time. In an instant your life could change and you could lose all feeling and function below the level of the injury.

Existing treatments are largely ineffective, so there is a pressing need for new regenerative therapies to repair tissue damage and restore function after spinal cord injury.

These new findings advance our understanding of the molecular mechanisms which may orchestrate the body’s remarkable capacity for natural repair.”

Professor Bradbury added:

“By enhancing this spontaneous response, we may be able to significantly improve spinal cord function after injury. Our research also has wider implications for other disorders of the central nervous system which share this demyelinating pathology, such as multiple sclerosis.”

Dr Katalin Bartus, also from the IoPPN at King’s College London, said:

“We hope this work will provide a platform for future research, in which it will be important to test how enhancing levels of neuregulin-1 will improve functional outcome after spinal cord injury.”

Florence R. Fricker, et al.
Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination
Brain; DOI: http://dx.doi.org/10.1093/brain/awt148 2279-2297

Photo: Tom Deerinck and Mark Ellisman, National Center for Microscopy and Imaging Research (NCMIR) Myelinated axons in a rat spinal root.