Glial Cells in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult motor neuron disease characterized by premature death of upper and lower motor neurons. Two percent of ALS cases are caused by the dominant mutations in the gene for superoxide dismutase 1 (SOD1) through a gain of toxic property of mutant protein. Genetic and chimeric mice studies using SOD1 models indicate that non-neuronal cells play important roles in neurodegeneration through non-cell autonomous mechanism. We review the contribution of each glial cell type in ALS pathology from studies of the rodent models and ALS patients. Astrogliosis and microgliosis are not only considerable hallmarks of the disease, but the intensity of microglial activation is correlated with severity of motor neuron damage in human ALS. The impaired astrocytic functions such as clearance of extracellular glutamate and release of neurotrophic factors are implicated in disease. Further, the damage within astrocytes and microglia is involved in accelerated disease progression. Finally, other glial cells such as NG2 cells, oligodendrocytes and Schwann cells are under the investigation to determine their contribution in ALS. Accumulating knowledge of active role of glial cells in the disease should be carefully applied to understanding of the sporadic ALS and development of therapy targeted for glial cells.

Far beyond the motor neuron: the role of glial cells in amyotrophic lateral sclerosis

“…Changes in the adequate formation and balance of the neuron-glia network and abnormal assembly of its components represent one of the main mechanisms related to different, slowly progressive, focal and global neuropsychiatric dysfunctions, such as ALS 10 . Although nearly all glial cells are involved in ALS pathogenesis, astrocytes and microglia have major roles 12 ( Figure 1). Protoplasmic and fibrous astrocytes, microglial cells and oligodendrocytes represent the major types of glial cells in the CNS and most non-neuronal pathological processes related to neurodegeneration involve these cell types.…”

“…As previously mentioned, astrocytes participate in glutamate clearance from the synaptic clefts providing more balanced levels of extracellular excitatory neurotransmission, the defective reuptake of which being the key mechanism in mouse models linked to EAAT2 transporter dysfunctions. It has also been proved in mutant SOD1 mice that astrocytes directly regulate the expression of glutamate receptor subunit GluR2 in AMPA receptors of motor neurons 12 . Other proven mechanisms included impaired release of multiple neurotrophic factors, including glial-derived neutrotrophic factor, ciliary neurotrophic factor, vascular endothelial growth factor and brain-derived neurotrophic factor 12 .…”

“…It has also been proved in mutant SOD1 mice that astrocytes directly regulate the expression of glutamate receptor subunit GluR2 in AMPA receptors of motor neurons 12 . Other proven mechanisms included impaired release of multiple neurotrophic factors, including glial-derived neutrotrophic factor, ciliary neurotrophic factor, vascular endothelial growth factor and brain-derived neurotrophic factor 12 . Astrocytes with SOD1 gene mutation produce reactive oxygen species and soluble molecules with a selective toxicity pattern to spinal cord motor neurons.…”

Dietary intake and zinc status in amyotrophic lateral sclerosis

“…It is believed that the combination of different mechanisms may be involved in motor neuron injury, including oxidative stress, glutamate excitotoxicity, mitochondrial dysfunction, neuroinflammation, apoptosis, protein aggregation and genetic mutations (3,4). In addition, zinc plays a key role in all these mechanisms associated with ALS pathogenesis (3).…”

The Role of TNF-Alpha in ALS: New Hypotheses for Future Therapeutic Approaches

“…Moreover, it is well known the implication of glial cells in the progression of neurodegeneration: they are involved in many types of damage, they migrate to the damaged cells and also they have a role in clearing the debris of the dead cells. Through such processes, microglia releases reactive oxygen species, proinflammatory cytokines, complement factors, and neurotoxic molecules, leading to further neuronal dysfunction and death (Heneka et al, 2011;Lasiene et al, 2011). In addition, the implication of the peripheral system and its participation in the cellular mechanisms that direct to neurodegeneration, as white blood cells, is well documented (Calvo et al, 2010;Ghezzi et al, 1998;Gowing et al, 2006).…”