Non-cell-autonomous pathogenic mechanisms in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset paralytic disorder, characterized mainly by a loss of motor neurons (MNs) in the CNS. Over the past decades, thanks to intense investigations performed in both in vivo and in vitro models of ALS, major progress has been made toward gaining insights into the pathobiology of this incurable, fatal disorder. Among these advances is the growing recognition that non-neuronal cells participate in the degeneration of MNs in ALS, which could transform our understanding of the neurobiology of disease and the ability to devise effective disease-modifying therapies. In this review, we examine the contribution of non-cell-autonomous processes to the pathogenesis of ALS, with a focus on glial cells and in particular on astrocytes.

Keywords: amyotrophic lateral sclerosis; astrocytes; microglia; motor neurons; neurodegeneration; neuroinflammation; non-cell autonomous.

Figure 1.. Illustration of the non-cell-autonomously based pathogenesis of amyotrophic lateral sclerosis (ALS).

Mounting evidence indicates that nonneuronal cells such as glial and immune cells could contribute to the degenerative process of ALS. However, according to this pathogenic hypothesis, not one but rather a host of different molecular mechanisms originating from non-neuronal cells may contribute to the demise of motor neurons (MNs). These non-cell-autonomous deleterious mechanisms can be divided into two main categories, which are not mutually exclusive: those due to a loss of beneficial effects (left box) and those due to a gain of toxic effects (right box). The non-cell-autonomous loss of beneficial effects involves a series of alterations in glial cells, which include reduced glutamate uptake and efflux lactate that is essential for MN energy supply, as well as impaired molecular injury responses. As for the non-cell-autonomous gain of toxic effects, it is believed that both inflammatory factors and non-inflammatory factors such as amyloid precursor protein (APP) fragment may be released by glial cells, which in turn engage death-signaling pathways in neighboring MNs. Abbreviations: C1Q, complement component 1q; DR6, death receptor 6; EphB1, ephrin type-B receptor 1; IL-1α, interleukin 1 alpha; MCT1, monocarboxylate transporter-1; NF-κB, nuclear factor kappa B; TNFα, tumor necrosis factor alpha.