August 6, 2014
MS Society-funded study identifies key molecules that may impair remyelination in MS
Brain cells transmit information through axons, the long fibre-like extensions of the cells wrapped in a substance called myelin. Myelin protects the brain cells while enhancing their capacity to communicate with each other. In MS, immune cells that normally act to protect our bodies cross into the brain and cause damage to myelin. The brain tries to repair itself through remyelination – or myelin repair - which occurs frequently in early MS.
Oligodendrocytes are myelin-producing cells in the brain. They first begin as oligodendrocyte progenitor cells (or OPCs, which are considered the younger version of oligodendrocytes). When myelin is damaged, OPCs can travel to the area of injury and mature into oligodendrocytes prior to rebuilding new myelin. As MS progresses, remyelination slows down and cells begin to degenerate and die – a process known as neurodegeneration. This is believed to result in the gradual accumulation of disability and ultimately the shift to progressive MS.
Netrin-1 is a protein involved in the development of the central nervous system (CNS), and is important in CNS recovery following nerve tissue injury. Recent evidence shows that netrin-1 is present in MS lesions, and may have an important role in the remyelination process, particularly by influencing the activity of OPCs. This observation prompted further work on netrin-1, including one study published online in Annals of Neurology.
The study, funded in part by the MS Society of Canada and led by Dr. Catherine Lubetzki from France in collaboration with MS Society-funded researcher Dr. Tim Kennedy and colleagues, involved a series of animal, cell and human-tissue based experiments which observed levels of netrin-1 in MS lesions and how it influence the myelin repair capabilities of OPCs.
Upon examination of human brain tissue, researchers observed high levels of netrin-1 in MS lesions, particularly from astrocytes. Further analyses showed OPCs bear molecules, called receptors, which can attach to netrin-1. This may allow netrin-1 to directly interact with OPCs and guide their behaviour.
Animal and cell experiments conferred similar findings, but interestingly also showed that the presence of netrin-1 repelled OPCs away from the lesion, resulting in less remyelination. Through sophisticated techniques, researchers were able to block the activity of netrin-1, which reversed the effect and enabled OPCs to migrate to the lesion.
Together, these findings suggest a likely mechanism through which the remyelination process may be hindered in MS. Repeated bouts of myelin damage may result in a depletion of OPCs within the lesion, an effect driven by netrin-1, ultimately impairing the remyelination process.
Disease-modifying treatments available for MS target components of the immune system thought to be responsible for myelin damage. What is less defined is how the central nervous system undergoes a process of repair to reconstruct the myelin that has been stripped away. Myelin repair is a critical and time-sensitive process - in order for repair to be successful, cell recruitment and myelin production must happen at the right place and time. Understanding which molecules promote or hinder these steps will help to develop therapies to enhance remyelination.
This study demonstrates that netrin-1 prevents OPCs from travelling to MS lesions, thus having a negative influence on myelin repair. This important discovery makes this protein a candidate therapeutic target for MS. The development of treatments which promote myelin repair will have a significant impact on reducing the accumulation of disability that often leads to progressive MS.
Tepavčević, V et al. Early netrin-1 expression impairs central nervous system remyelination. Annals of Neurology 2014 June 18 [Epub ahead of print].