Review A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis Luis H. Barbeito a, * , Mariana Pehar a,b , Patricia Cassina b , Marcelo R. Vargas a , Hugo Peluffo b , Liliana Viera c , Alvaro G. Este ´vez c , Joseph S. Beckman d a Departamento de Neurobiologı ´a Celular y Molecular, Instituto de Investigaciones Biolo ´gicas Clemente Estable, Avenida Italia 3318-CP 11600, Montevideo, Uruguay b Departamento de Histologı ´a y Embriologı ´a, Facultad de Medicina, Universidad de la Repu ´blica, Montevideo, Uruguay c Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL, USA d Linus Pauling Institute, Environmental Health Sciences Center, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA Accepted 27 May 2004 Available online 5 August 2004 Abstract A strong glial reaction typically surrounds the affected upper and lower motor neurons and degenerating descending tracts of ALS patients. Reactive astrocytes in ALS contain protein inclusions, express inflammatory makers such as the inducible forms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2. In this review, we discuss the evidence sustaining an active role for astrocytes in the induction and propagation of motor neuron loss in ALS. Available evidence supports the view that glial activation could be initiated by proinflammatory mediators secreted by motor neurons in response to injury, axotomy or muscular pathology. In turn, reactive astrocytes produce nitric oxide and peroxynitrite, which cause mitochondrial damage in cultured neurons and trigger apoptosis in motor neurons. Astrocytes may also contribute to the excitotoxic damage of motor neurons by decreasing glutamate transport or actively releasing the excitotoxic amino acid. In addition, reactive astrocytes secrete pro-apoptotic mediators, such as nerve growth factor (NGF) or Fas-ligand, a mechanism that may serve to eliminate vulnerable motor neurons. The comprehensive understanding of the interactions between motor neurons and glia in ALS may lead to a more accurate theory of the pathogenesis of the disease. D 2004 Elsevier B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Neuromuscular diseases Keywords: Amyotrophic lateral sclerosis; Astrocytes; Motor neurons; Nitric oxide; Peroxynitrite Contents 1. Introduction ........................................................... 264 2. Astrocyte pathology in ALS ................................................... 264 3. The origin of astrocytosis in ALS ................................................ 265 3.1. Aging ........................................................... 265 3.2. Oxidative stress and peroxynitrite ............................................ 266 3.3. Axotomy and neuronal damage .............................................. 266 4. Neurotoxic potential of reactive astrocytes in ALS ....................................... 267 4.1. Downregulation of astrocytic glutamate transporters ................................... 267 4.2. Cytokine production by astrocytes ............................................ 267 4.3. Production of nitric oxide and peroxynitrite ....................................... 268 4.4. Production of apoptotic factors .............................................. 268 0165-0173/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2004.05.003 * Corresponding author. Tel.: +598-2-487-16-16; fax: +598-2-487-55-48. E-mail address: lbarb@iibce.edu.uy (L.H. Barbeito). www.elsevier.com/locate/brainresrev Brain Research Reviews 47 (2004) 263 – 274