The Na⁺/Ca²⁺ exchangers in demyelinating diseases

Highlights

• This review describes the role of NCX exchanger subtypes in demyelinating diseases.

• Dysfunctional NCX activity contribute to axonal pathology in demyelinated axons.

• NCX activity is required for myelin synthesis in oligodendroglia.

• Defining the role of NCXs will help to identify neuroprotective/remyelinating treatments.

Abstract

Intracellular [Na⁺]_i and [Ca²⁺]_i imbalance significantly contribute to neuro-axonal dysfunctions and maladaptive myelin repair or remyelination failure in chronic inflammatory demyelinating diseases such as multiple sclerosis. Progress in recent years has led to significant advances in understanding how [Ca²⁺]_i signaling network drive degeneration or remyelination of demyelinated axons.

The Na⁺/Ca²⁺ exchangers (NCXs), a transmembrane protein family including three members encoded by ncx1, ncx2, and ncx3 genes, are emerging important regulators of [Na⁺]_i and [Ca²⁺]_i both in neurons and glial cells. Here we review recent advance highlighting the role of NCX exchangers in axons and myelin-forming cells, i.e. oligodendrocytes, which represent the major targets of the aberrant inflammatory attack in multiple sclerosis. The contribution of NCX subtypes to axonal pathology and myelin synthesis will be discussed. Although a definitive understanding of mechanisms regulating axonal pathology and remyelination failure in chronic demyelinating diseases is still lacking and requires further investigation, current knowledge suggest that NCX activity plays a crucial role in these processes. Defining the relative contributions of each NCX transporter in axon pathology and myelinating glia will constitute not only a major advance in understanding in detail the intricate mechanism of neurodegeneration and remyelination failure in demyelinating diseases but also will help to identify neuroprotective or remyelinating strategies targeting selective NCX exchangers as a means of treating MS.

Introduction

Multiple Sclerosis (MS) is the most common demyelinating disorders leading to chronic inflammation, oligodendroglia and neuronal degeneration in the brain and/or spinal cord. The pathological hallmark of the disease is the characteristic formation of “plaques” or “lesions” clearly visible with magnetic resonance imaging (MRI) and consisting in multiple focal areas of myelin loss accompanied by variable inflammation, gliosis, phagocytic activity, and axonal damage [1,2]. Although the disease pathogenesis remains unclear, it is believed that the clinical manifestations of MS result from a complex interaction between genetic and environmental factors that lead to an immune response against myelin self-antigens. Hence, oligodendrocytes, the cells that make and maintain the myelin sheets around axons, are the main target of the aberrant immune attack leading to axonal demyelination [3,4]. Nevertheless, when axons are not irreversible damaged, demyelination may be followed by a spontaneous regenerative process, called remyelination, in which new myelin is restored to the axons and a proper axonal conduction and trophic support is reestablished. Repair processes require the activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs) that, after migrating into the lesion, proliferate and differentiate in myelinating oligodendrocytes [5]. This myelin repair process contributes to clinical recovery after a relapse in relapsing-remitting MS [6,7]. As the disease progresses, the remyelination capacity of OPCs diminishes and chronically demyelinated axons became more vulnerable to degeneration. Indeed, as initial compensatory mechanism to preserve conductance, demyelinated axons undergo considerable molecular reorganizations by expressing and redistributing several ion channels that perpetuate ionic dyshomeostasis and facilitate permanent axonal damage. Neurodegeneration and failure of remyelination characterize the progressive MS forms and contribute to the accumulation of neurological disability without clinical recovery [[8], [9], [10]].

MS therapies are primarily immunomodulatory, but a significative effort is underway to develop molecules with the potential to stimulate myelin repair or halt the neurodegenerative processes, particularly for the treatment of progressive forms of MS, for which current therapies are relatively ineffective. Restoring remyelination, indeed, is an important therapeutic goal to restore neuronal function, prevent neurodegeneration and progression of clinical disability in MS and other myelin diseases [[11], [12], [13]].

Present findings suggest that [Na⁺]_i and [Ca²⁺]_i imbalance significantly contributes not only to neuro-axonal dysfunctions, but also to maladaptive myelin repair or remyelination failure during chronic inflammation. In line, brain sodium MRI demonstrated that total tissue sodium concentration, a combined measure of the intracellular and extracellular sodium, increases in brain MS lesions and is higher in the brain of MS persons with greater disability and in progressive disease courses, thus indicating significant correlation with neuro-axonal dysfunction, failure of remyelination and disease progression [14,15].

Progress in recent years has led to significant advances in understanding how [Na⁺]_i and [Ca²⁺]_i signaling network drives degeneration or remyelination of demyelinated axons [9,[16], [17], [18]].

The Na⁺/Ca²⁺ exchangers (NCXs), a transmembrane protein family including three members encoded by ncx1, ncx2, and ncx3 genes, are emerging important regulators of sodium and calcium homeostasis in physiological and pathophysiological conditions, including demyelinating diseases [[19], [20], [21], [22], [23], [24], [25]]. Indeed, it has been proposed that dysfunctional NCX1 exchangers contribute to detrimental calcium overload and axonal degeneration in MS lesions [[26], [27], [28], [29], [30]]. At variance, a number of studies in the last decade highlight the protective function of NCX3 exchanger in several disease states, including demyelinating disorders [[31], [32], [33], [34], [35], [36], [37]], and suggest an important functional role of this exchanger for myelin synthesis in oligodendroglia [25,33,[38], [39], [40]].

In the next sections we will summarize recent advance highlighting the role of NCX exchangers in demyelinated axons and oligodendroglia. In addition, we will discuss how NCX subtypes may contribute to axonal pathology and myelin repair in a chronic demyelinating disease such as MS.