Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Toxicity Pathways in ALS Neurodegenerative Dis 2005;2:139–146 DOI: 10.1159/000089619 Complexity of Astrocyte-Motor Neuron Interactions in Amyotrophic Lateral Sclerosis Mariana Pehar a Marcelo R. Vargas a Patricia Cassina b Ana G. Barbeito b Joseph S. Beckman c Luis Barbeito a a Departamento de Neurobiología Celular y Molecular, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, and b Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; c Linus Pauling Institute, Environmental Health Sciences Center, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oreg., USA dant and cytoprotective enzymes such as heme oxygen- ase-1 and a group of enzymes involved in glutathione metabolism that prevent motor neuron degeneration. However, prolonged stimulation with FGF-1 or SOD-me- diated oxidative stress in astrocytes may disrupt the nor- mal neuron-glia interactions and lead to progressive neuronal degeneration. The re-expression of p75 neuro- trophin receptor and neuronal NOS in motor neurons in parallel with increased NGF secretion by reactive astro- cytes may be a mechanism to eliminate critically dam- aged neurons. Consequently, astrocyte activation in ALS may have a complex pathogenic role. Copyright © 2005 S. Karger AG, Basel Introduction Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the progressive and selective degenera- tion of cortical, bulbar and spinal motor neurons. The characteristic ALS symptoms of spasticity, paralysis and atrophy of skeletal muscles reflect the loss of both upper and lower motor neurons. Because the degeneration of motor neurons is so blatant, research on ALS has been Key Words Amyotrophic lateral sclerosis  Astrocytes  Motor neurons  Fibroblast growth factor  Nerve growth factor Abstract Neurons and surrounding glial cells compose a highly specialized functional unit. In amyotrophic lateral sclero- sis (ALS) astrocytes interact with motor neurons in a complex manner to modulate neuronal survival. Experi- ments using chimeric mice expressing ALS-linked muta- tions to Cu,Zn superoxide dismutase (SOD-1) suggest a critical modulation exerted by neighboring non-neuro- nal cell types on disease phenotype. When perturbed by primary neuronal damage, e.g. expression of SOD-1 mu- tations, neurons can signal astrocytes to proliferate and become reactive. Fibroblast growth factor-1 (FGF-1) can be released by motor neurons in response to damage to induce astrocyte activation by signaling through the re- ceptor FGFR1. FGF-1 stimulates nerve growth factor (NGF) expression and secretion, as well as activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) tran- scription factor. Nrf2 leads to the expression of antioxi- Diseases Luis Barbeito Departamento de Neurobiología Celular y Molecular Instituto de Investigaciones Biológicas Clemente Estable Avenida Italia 3318, CP 11600 Montevideo (Uruguay) Tel. +598 2 4871616, Fax +598 2 4875548, E-Mail lbarb@iibce.edu.uy © 2005 S. Karger AG, Basel Accessible online at: www.karger.com/ndd