Trophic Factor Production by Glial Cells in the Treatment of Amyotrophic Lateral Sclerosis

Review Article

Austin J Biomed Eng. 2014;1(5): 1001.

Trophic Factor Production by Glial Cells in the Treatment of Amyotrophic Lateral Sclerosis

Dennys CN, Franco MC and Estévez AG*

Department of Biomedical Sciences, University of Central Florida, USA

*Corresponding author: :Estévez AG, Burnett School of Biomedical Science, University of Central Florida, 6900 Lake Nona Blvd, Orlando, FL 32827, USA.

Received: August 10, 2014; Accepted: September 08, 2014; Published: September 10, 2014


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with unknown pathogenic causes. The identification of mutated genes in familial forms of ALS has lead to the development of animal models to study the mechanisms of motor neuron death. Transgenic animal models and human patients show that glutamate excitotoxicity, oxidative stress, protein aggregation and inflammation are hallmarks of the disease. Here we discuss the role of activated glial cells, specifically astrocytes and microglia on the disease pathogenesis and progression. Additionally, we discuss the current evidence showing that the induction of trophic factor production by glial cells may be an effective therapeutic strategy for the treatment of ALS.

Keywords: Amyotrophic lateral sclerosis; Astrocytes; Microglia; Trophic factors


ALS: Amyotrophic Lateral Sclerosis; SOD: Superoxide Dismutase; GLT-1: Glutamate Transporter-1; EAAT2: Excitatory Amino Acid Transporter; AMPA: α-Amino-3-Hydroxy-5-Methyl- 4-Isoxazolepropionic Acid; Hsp90: Heat Shock Protein 90; Nrf2: Nuclear Factor Like 2; NOX: NADPH Oxidase; MCP1: Monocyte Chemo Attractant Protein; CCL5: Chemokine (CC motif) Ligand 5; TNF: Tumor Necrosis Factor; IL-1A: Interleukin-1A; IL-1B: Interleukin-1B; IL-1RA: Interleukin-1RA; M-CSF: Macrophage Colony Stimulating Factor; COX-2: Cyclooxygenase-2; iNOS: inducible nitric oxide synthase; Arg1: arginase-1; BDNF: brain derived neurotrophic factor; GDNF: Glial Derived Neurotrophic Factor; CNTF: Ciliaryneurotrophic Factor; VEGF: Vascular Endothelial Growth Factor; IGF1: Insulin Growth Factor-1; Hsp70: Heat Shock Protein 70


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting 2 people every 100:000 populations. Most of the affected individuals live an average of 3-5 years after diagnosis: but some individuals live longer. Approximately 10% of cases are hereditary or familial and are referred as familial ALS. The other 90% of ALS cases are sporadic: for which the causes of the disease remain unknown. The identification of genes which mutations are associated to ALS allowed the development of transgenic mouse models of the disease. The discovery that 20-30% of the familial cases of ALS were linked to mutations in the gene of the antioxidant enzyme superoxide dismutase (SOD) lead to the development of a variety of transgenic mouse models that develop a disease with the general characteristics and symptoms of ALS[1-10]. In spite of the initial enthusiasm that the transgenic model would provide a rapid understanding of the disease leading to a cure: 20 years later there are no new treatments for ALS. The transgenic mouse models have become under attack as a tool to study the disease. Transgenic ALS mouse models over expressing mutant SOD not only have failed as a tool to help elucidate the mechanism of SOD toxicity: but also failed to be predictive for the development of successful human therapies.

However: transgenic animals recapitulate many of the characteristics of the disease and have become useful tools to elucidate the role of other cell types in the pathogenesis of ALS. It is now widely accepted that motor neurons are not the only cell type affected in ALS. During symptom onset and as disease progresses there is an increase in activated astrocytes and microglia [11,12]. These cells are also activated in the spinal cord of post mortem tissues of ALS patients [13-17]. Recently many studies have focused on the contribution of glial cells to disease onset and progression.

Amyotrophic Lateral Sclerosis

A number of different hypotheses have been developed over the years to explain motor neuron degeneration in ALS, including glutamate excitotoxicity, oxidative stress: protein aggregation and inflammation (Figure 1) [18]. The first hypothesis to explain the pathology of ALS was glutamate excitotoxicity [19]. In the G93A SOD mouse and rat ALS models, the levels and activity of glial glutamate transporter (GLT-1) were reduced [20-23]. Shortly after, a reduction in the expression of the human equivalent of GLT-1: EAAT-2, was observed in the motor cortex and spinal cord of ALS patients [24,25]. In addition, glutamate levels in the cerebral-spinal fluid were increased in ALS patients [26,27]. The decrease of EAAT- 2expressionwas proposed as the cause of extracellular glutamate accumulation: which in turn stimulated motor neuron degeneration through hyper activation of the AMPA glutamate receptors [28]. A similar decrease in glutamate transporter activity and increased levels of glutamate is present in the cerebral spinal fluid and plasma of mutant SOD mouse models [7,21,22,29]. Suggesting that the selective loss of glial GLT-1 causes the increase in glutamate levels both in vivo and in vitro [30]. Further support comes from delayed motor neuron degeneration in G93A mutant SOD transgenic models of ALS over expressing GLT-1[31], suggesting that restoration of glutamate uptake can delay disease progression. These observations were among the first to imply that glial cell dysfunction contributes to the progressive loss of motor neurons in ALS.

Citation: Dennys CN, Franco MC and Estévez AG. Trophic Factor Production by Glial Cells in the Treatment of Amyotrophic Lateral Sclerosis. Austin J Biomed Eng. 2014;1(5): 1001. ISSN: 2381-9081.