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The Journal of Neuroscience, January 21, 2009, 29(3):610-619; doi:10.1523/JNEUROSCI.5443-08.2009
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Neurobiology of Disease
Dysregulation of Iron Homeostasis in the CNS Contributes to Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis
Suh Young Jeong,1 Khizr I. Rathore,1 Katrin Schulz,1 Prem Ponka,2 Paolo Arosio,3 andSamuel David1 1Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4, 2Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2, and 3Dipartimento Materno Infantile e Tecnologie Biomediche, Università di Brescia, 25123 Brescia, Italy
Correspondence should be addressed to Dr. Samuel David, Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Livingston Hall, Room L7-210, 1650 Cedar Avenue, Montreal, Quebec, Canada H3G 1A4. Email: sam.david{at}mcgill.ca
Amyotrophic lateral sclerosis (ALS), characterized by degeneration of spinal motor neurons, consists of sporadic and familial forms. One cause of familial ALS is missense mutations in the superoxide dismutase 1 (SOD1) gene. Iron accumulation occurs in the CNS of both forms of ALS; however, its contribution to the pathogenesis of ALS is not known. We examined the role of iron in a transgenic mouse line overexpressing the human SOD1G37R mutant. We show that multiple mechanisms may underlie the iron accumulation in neurons and glia in SOD1G37R transgenic mice. These include dysregulation of proteins involved in iron influx and sensing of intracellular iron; iron accumulation in ventral motor neurons secondary to blockage of anterograde axonal transport; and increased mitochondrial iron load in neurons and glia. We also show that treatment of SOD1G37R mice with an iron chelator extends life span by 5 weeks, accompanied by increased survival of spinal motor neurons and improved locomotor function. These data suggest that iron chelator therapy might be useful for the treatment of ALS.
Key words: ALS; iron; neurodegeneration; free radicals; spinal cord; neuron death
Received Nov. 11, 2008; accepted Dec. 7, 2008.
Correspondence should be addressed to Dr. Samuel David, Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Livingston Hall, Room L7-210, 1650 Cedar Avenue, Montreal, Quebec, Canada H3G 1A4. Email: sam.david{at}mcgill.ca
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[Abstract] [Full Text] [PDF]
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