The pathology of multiple sclerosis (MS) involves not only the loss of myelin sheets around the axons of neurons, but also the fragmentation of the axons themselves. At ECTRIMS 2018, novel targets to combat neuronal degeneration in MS were discussed, and an intriguing new hypothesis was presented.
As a prelude into the topic, Prof. Martin Kerschensteiner (Munich, Germany) introduced the concept of neuronal degeneration as a multi-stage process. According to a hypothesis stemming from animal studies, inflammatory mediators and energy deficiency lead to ‘swelling’ of the axon, which can last up to 3–4 days. This is followed by the axons fragmenting beyond repair. While there are many potential mediators that can cause the axonal swelling, Prof. Kerchensteiner’s work focuses on neuronal ‘calcium overload’, which may cause an energetic imbalance leading to axonal damage and swelling.
Dr Adrian-Minh Schumacher, a post-doc in the laboratory of Prof. Kerschensteiner, elaborated on the topic by presenting his latest empirical results. In a mouse model of acute cortical MS, Dr Schumacher observed a loss of connections between neurons and a decreased overall neuronal activity after injection of inflammatory mediators (cytokines) into the brain. Further, he observed a calcium overload in the neurons that suffered the loss of connections, meaning that the calcium overload could tag neuronal connections for removal.
Trying to identify a way to target this pathway of neuronal damage, he found that phagocytic cells of the immune system seemed to respond to this ‘calcium signal’ by engulfing and removing parts of the neuron. Further, in an effort to translate these findings into clinical applications, the group were able to rescue this type of neuronal damage by inhibiting the activity of phagocytic immune cells with a small molecule.
Will inhibiting the activity of specific types of immune cells reduce the loss of neurons in patients with multiple sclerosis? Can we target this mechanism of neuronal swelling in other ways, before the fragmentation begins? Considering the clinical impact of neurodegeneration, particularly in progressive stages of MS, further experiments and clinical studies are clearly merited.