Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.

Bi-Directional Communication Between Neurons and Astrocytes Modulates Spinal Motor Circuits

“…Furthermore, if spinal cord astrocytes are indeed active participants in the locomotor CPG, then it is likely their role is driven by neuronallyderived signals, which remain to be identified. Given growing evidence that astrocytes play a role in a host of neurological and neurodegenerative diseases, including chronic pain (Ji et al, 2006;Gao and Ji, 2010), spinal cord injury (Okada et al, 2006) and Amyotrophic Lateral Sclerosis (ALS; Phatnani et al, 2013;Pehar et al, 2018), identifying the physiological roles of astrocytes within spinal circuits, and the signaling mechanisms involved, could pave the way for the development of novel therapeutic strategies.…”

Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS‐linked mutant SOD1

“…In line with these observations, astrocytes differentiated from human post mortem ALS spinal cord-derived progenitor cells and astrocytes obtained from the transdifferentiation of fibroblasts from FALS and SALS patients are also toxic for motor neurons in coculture (8,9). Moreover, therapeutic strategies aimed at reducing astrocyte-mediated toxicity increase motor neuron survival and improve motor performance in ALS mouse models (10)(11)(12).…”

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

“…However, the key points to bear in mind during a perusal of the following sections of this article are that many of the factors underpinning the loss of homeostatic functions normally exerted by astrocytes in their physiological state stem from the changes in transcription orchestrated by the chronic activation of the pathways and transcription factors discussed above and/or the ensuing increases in levels of PICs, ROS, and RNS. These adversely affect the transcription and/or function of crucial membrane receptors and impair mitochondrial respiration and dynamics [59,172,173]. The importance of the latter is difficult to overemphasize as the homeostatic roles of astrocytes depend on adequate performance of mitochondria [55,56,174], and on a wider note, a host of neural-glial interactions also depend on optimal mitochondrial function [175].…”