The traditional classification of multiple sclerosis (MS) into distinct subtypes – relapsing-remitting, primary progressive, and secondary progressive – has been challenged by consistent evidence of early and continuous neurodegeneration in MS [1]. A diffuse relentless smouldering disease activity affects the whole central nervous system (CNS) leading to a gradual accumulation of disability [2].
The term smoldering activity refers to the chronic pathobiological processes within the CNS that go beyond acute inflammation and are associated with neurodegeneration [3, 4]. The underlying causes of persistent neurodegeneration in MS are not yet fully understood. Several pathological mechanisms within the CNS contribute to smoldering-associated worsening (SAW) [5]. Understanding and targeting these mechanisms represents the next therapeutic challenge [6].
Professor Manuel Friese from the University Medical Center of Hamburg tells us, “A low-grade inflammation probably starts at the beginning of the disease and persists for many years, even decades. This ongoing inflammation may be the driving force of the disease. And then on top of that, some individuals experience relapses, associated with an influx of immune cells. The key question is: How does low-grade inflammation lead to neurodegeneration? This topic remains under debate. If we manage to stop smoldering inflammation, could we prevent neurodegeneration? Or, once neurodegeneration is triggered, will it continue despite the efforts to dampen down smoldering inflammation? I believe that, once it starts, smoldering inflammation kicks off autonomous reactions and modifications in the neurons that cannot be turned off. After that, something changes fundamentally in the way neurons react to the environment, and they will eventually degenerate.”
Smouldering disease activity involves low-grade inflammation and neuronal deregulation [1]. Gaining insight into how neurons become deregulated could help enhance neuronal resilience and counteract progression [1].
Inflammation is a vital biological mechanism that serves to restore brain homeostasis when it is threatened by significant challenges like injuries or infections [7]. Inflammation in the CNS induces various molecular changes. Immune cells produce substances, such as cytokines and glutamate, which alter the metabolism of neurons [8]. In the short term, these processes play a crucial role in protecting the tissues and resolving the injury. However, in the long term they can trigger a cascade of stress responses [8].
Energy metabolism in neurons
“Energy metabolism is a central theme”, Professor Friese says, “When viruses enter the brain, they need to be eliminated or modified to prevent further spread. And many viruses rely on the brain’s energy to replicate within neurons. Therefore, neurons probably respond to inflammation by shutting down energy production and, in some cases, retracting their synapses not to spread infection from one neuron to the other. This is an evolutionary response, as neurons associate inflammation with infection. However, the neural reaction remains the same also in the case of chronic inflammation caused by a deregulation of the immune system – when there is no actual infection. It is important to study how neurons react to infections and understand the underlying mechanisms. One key aspect of this response is limiting energy production to contain potential infections. While this can be beneficial in the short term, prolonged inflammation can lead to long-term energy depletion. Therefore, neurons must entirely reprogram their energy production and usage. Neurons are reprogrammed to produce energy in a different way, but eventually they will have a massive shortage that will ultimately lead to neural degeneration.”
The role of mitochondria
Inflammation in MS exposes neurons to many external inputs, such as glutamate, cytokines, energy shortage, that disrupt homeostasis and initiate the neural stress response [1]. There are then amplifiers, including alterations of neuronal transport, that enhance the neural deregulation upon internal cues [1].
Mitochondria play an essential role in maintaining neuronal energy homeostasis [9]. In particular, axons rely on various energy sources, including the local supply provided by mitochondria [10]. The distribution and shape of mitochondria in axons can change to adapt to various conditions, such as ageing [10]. Mitochondria react also to demyelination. Following demyelination, the energy balance in axons is disrupted [10]. Mitochondria respond with a series of processes called “axonal response of mitochondria to demyelination” (ARMD) [11]. Their number, activity, and transport speed increase, and they are relocated from the neural soma to the axon [10].
“A myelinated axon is metabolically very efficient. Under normal conditions, mitochondria, as the primary energy producers, disappear from the axon as they are not really needed”, Professor Don Mahad from the University of Edinburgh tells us, “However, when demyelination occurs, the energy demand increases. To meet this demand, more mitochondria are needed in the axon. The neuronal cell body has to produce more mitochondria, and they have to move to the axon, specifically to the demyelinated segment, to supply extra energy. This is what we call ARMD. This compensatory process is not instantaneous. It takes time. In animal models it takes days for the mitochondria to reach the demyelinated segment. During this critical period, the axon is exceptionally vulnerable, because the energy demand goes up, but the energy supply is still not there. This is when the axon degenerates and this is when we have to act with neuroprotective strategies.”
ARMD can be accelerated by increasing the transport of mitochondria from the soma to the axon of the neuron and by increasing the production of mitochondria within neurons [10]. This could be one promising strategy to protect the neuron and prevent degeneration.
Therapeutic challenges
There may be multiple ways in which the processes within the CNS responsible for neurodegeneration in MS could be modified. And probably, multiple drugs will be used together to target different aspects of the disease [6].
Professor Friese says, “We need more targeted treatments that focus on inhibiting the input of stressors. It is essential to manage and reduce the stressors to prevent smoldering installation. That needs to be done wherever it is happening, we need to get rid of the input and improve the neuron’s ability to use energy. For example, metformin appears to be heading in this direction by optimising energy metabolism.”
Future studies are needed to target neurodegeneration as early as possible.
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Written by Stefania de Vito
Special thanks to Professor Manuel Friese (University Medical Center Hamburg) and Professor Don Mahad (The University of Edinburgh) for their insights.
References
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