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.

Keywords: Astrocytes; amyotrophic lateral sclerosis; gliosis; motor neuron; neurodegeneration; oxidative stress.

Figure 1

Schematic representation of potential pathways involved in astrocyte-mediated motor neuron death in ALS. Astrocytes in ALS display reduced ability to provide metabolic support to motor neurons and to effectively regulate the extracellular levels of ions and neurotransmitters. Impaired glutamate transport in astrocytes leads to accumulation of excitotoxic levels of extracellular glutamate. Excitotoxicity is further facilitated by increased permeability of AMPA receptors to calcium as a consequence of decreased expression and pre-mRNA editing of GluA2 AMPA receptor subunits in motor neurons. In addition, the potassium buffering capacity of astrocytes is negatively affected by the reduced expression of the astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1). The concomitant rise in extracellular potassium levels contributes to neuronal hyperexcitability and further decreases the electrogenic uptake of glutamate. Reactive astrocytes display increased production of nitric oxide (^·NO) due to iNOS upregulation. Moreover, mitochondrial dysfunction leads to increased production of superoxide (O₂^·-) and the subsequent formation of peroxynitrite (ONOO⁻), leading to oxidative and nitrative stress. Nitric oxide and peroxynitrite can diffuse across cellular membranes to directly affect mitochondrial function and induce oxidative and nitrative stress in motor neurons. Reduced Nrf2 expression by motor neurons could further aggravate this process. Increased levels of nitric oxide also sensitize motor neurons to the apoptotic signaling mediated by FasL/Fas and NGF/p75^NTR. The release of other neurotoxic factors by ALS-astrocytes has also been described (see text for further details). The cross-talk between astrocytes and microglia is affected by the release of different proinflammatory mediators that promote a neurotoxic phenotype in both cell types (see text for further details).