Astrocyte dysfunction and motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS)

Luis Barbeito

Institut Pasteur de Montevideo, Uruguay.

Accumulated evidence support the view that astrocytes actively modulate motor neuron loss in familial amyotrophic lateral sclerosis (ALS) models. This is consistent with the fact that selective motor neurons death in ALS is a non-cell autonomous process. Astrocytes expressing SOD1 mutation are able induce death of motor neurons in vitro. Such pathogenic feature of astrocytes is dependent of a characteristic inflammatory-like astrocytic phenotype triggered by SOD1 mutations. Interestingly, the same phenotype can also be induced in non-transgenic astrocytes by other stimuli such as FGF-1, LPS and peroxynitrite. Experimental evidence that astrocytes expressing SOD1 mutation are not intrinsically neurotoxic to motor neurons but rather display the ability to eliminate only vulnerable motor neurons. Our working hypothesis is based on following assumptions: i) the motor neuron response to disease is shaped by the interactions with adjacent astrocytes. Hence, both cell types should be considered heavily involved in the neurodegenerative process by complex and yet not well-understood non-cell autonomous mechanisms. ii) Astrocytes constitute a renewable and plastic cell type within the CNS; in response to primary motor neuron damage astrocytes are activated to adopt a wide variety of phenotypes, some of which can stimulate the death of motor neurons at risk, thus mediating progressive disease. iii) At the same time, other and perhaps co-existing astrocytes exhibit a regenerative or neuroprotective phenotype, characterized by the ability to resist damage, downregulate inflammation and support survival of adjacent neurons. We propose that the understanding of glial cell behavior in ALS and their influence on motor neuron survival/death may lead to the development of new therapeutic intervention in ALS.