Engine Failure in Axo-Myelinic Signaling: A Potential Key Player in the Pathogenesis of Multiple Sclerosis

Abstract

Multiple Sclerosis (MS) is a complex and chronic disease of the central nervous system (CNS), characterized by both degenerative and inflammatory processes leading to axonal damage, demyelination, and neuronal loss. In the last decade, the traditional outside-in standpoint on MS pathogenesis, which identifies a primary autoimmune inflammatory etiology, has been challenged by a complementary inside-out theory. By focusing on the degenerative processes of MS, the axo-myelinic system may reveal new insights into the disease triggering mechanisms. Oxidative stress (OS) has been widely described as one of the means driving tissue injury in neurodegenerative disorders, including MS. Axonal mitochondria constitute the main energy source for electrically active axons and neurons and are largely vulnerable to oxidative injury. Consequently, axonal mitochondrial dysfunction might impair efficient axo-glial communication, which could, in turn, affect axonal integrity and the maintenance of axonal, neuronal, and synaptic signaling. In this review article, we argue that OS-derived mitochondrial impairment may underline the dysfunctional relationship between axons and their supportive glia cells, specifically oligodendrocytes and that this mechanism is implicated in the development of a primary cytodegeneration and a secondary pro-inflammatory response (inside-out), which in turn, together with a variably primed host’s immune system, may lead to the onset of MS and its different subtypes.

Myelin lipids as nervous system energy reserves

“…Our findings have also relevance for neurodegenerative diseases. In multiple sclerosis (MS), axon loss has been attributed to an energy failure 48 which could further drive demyelination. Many neuronal disorders, including Alzheimer's disease, have been associated with hypometabolism 9 and white matter abnormalities 8,49,50 .…”

Diabetes Mellitus: A path to Amnesia, Personality and Behavior Change.

“…Neurons and glia provide trophic support to vascular cells, and therefore damage of these supporting cells results in atrophy of endothelial cells and rarefaction of microvasculature [36,92]. Damage of myeline sheath and demyelination of axons is one of the outcomes of inflammatory state and oxidative stress [93,94]. Demyelination leads to disruption of the integrity of axons, exposure of axons to damaging effects of free radicals and cytokines in the brain's white matter [95,96].…”

“…Advanced glycation end products formed in diabetic subjects, resulting in secretion of MMP 9 from endothelial cells and BDNF receptor TRKB cleavage, thus decreasing neurotrophin signaling [91]. Myelin sheath damage and demyelination of axons are some of the inflammatory states and oxidative stress [93,94]. Demyelination leads to disruption of the integrity of axons, exposure of axons to damaging effects of free radicals and cytokines in the brain's white matter [95,96].…”

Diabetes Mellitus: A Path to Amnesia, Personality, and Behavior Change

“…Neurons and glia provide trophic support to vascular cells, and therefore damage of these supporting cells results in atrophy of endothelial cells and rarefaction of microvasculature [47,109]. Loss of myelin sheath's normal physiology and anatomy, including demyelination of axons, has been reported as one of the dangerous outcomes of the inflammatory process and ROS [110,111]. Demyelination leads to disruption of the integrity of axons exposure to the damaging effects of free radicals and cytokines in the brain's white matter [112,113].…”