Discovered a new demyelination mechanism in Multiple Sclerosis

A group of researchers from the IRCCS Ospedale San Raffaele in Milan, coordinated by Cinthia Farina, head of the Immunobiology of Neurological Disorders Lab, identified in the malfunctioning of copper transport a new pathological process underlying the demyelination in patients suffering from multiple sclerosis.

The discovery, published in PNAS, concerns in particular the role of the TrkB receptor, which is abnormally expressed by astrocytes in brain areas affected by the disease. This receptor controls the release of copper into the white matter: like other heavy metals – such as iron or zinc – high concentration of copper can be toxic and promote cell death. 

The results shed new light on the pathophysiological mechanisms underlying multiple sclerosis and identify a new therapeutic target: the TrkB receptor, which plays a key role in maintaining copper homeostasis.

The importance of copper and the role of astrocytes

Farina PNAS Farina PNAS

Multiple Sclerosis active lesion, showing co-expression of the CTR1 copper transporter (green) and the neurotrophin receptor TrkB (red) on reactive astrocytes

Copper plays a key physiological role in different tissues and organs. One of its main functions is to bind proteins involved in energy metabolism and those with antioxidant action. As with other metals, however, copper can be toxic in high concentrations and therefore needs to be finely regulated. This is why copper homeostasis requires tight control of the metal transport, absorption, release and storage within the cells of the nervous system.

Researchers at San Raffaele confirmed, first in vitro and then in vivo, that astrocytes (and in particular the TrkB receptors present on their surface) are involved in the regulation of copper in the central nervous system (CNS). These receptors are usually activated by neurotrophins – proteins thought to be beneficial because they promote neuroprotection and tissue regeneration.

The link between TrkB receptors and demyelination

"We have shown that TrkB receptors can be activated in the pathological context of MS even in the absence of neurotrophins, because they respond to other signals, both inflammatory and toxic. Their dysfunctional activation mediates the demyelination process and supports glial functions necessary for scar formation in the white matter," specifies Emanuela Colombo, first author of the study.

Data from both in vitro cultured astrocytes and experimental models suggest a clear link between TrkB over-expression and excessive copper release by astrocytes. Copper release was then correlated with the loss of myelin, typical of the pathological process of multiple sclerosis.

"The results of our research underline for the first time the importance of studying copper transport in the central nervous system of multiple sclerosis patients. Restoring proper copper homeostasis in the white matter – in particular by focusing on TrkB receptors – could represent, in the near future, a new therapeutic strategy to treat the disease" concludes Cinthia Farina.

The study was made possible thanks to funding from the Italian Ministry of Health and the Italian Multiple Sclerosis Foundation (IMF).