Mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS). Studies in chimeric or conditional mutant mice indicate that non- neuronal cells play an important role in ALS-related neurodegeneration. We and others find that mutant SOD1 astrocytes can kill motor neurons. However, mutant astrocytes do not kill spinal interneurons, which are also spared in the spinal cord of ALS patients. Here, we seek to investigate further the selective toxic effects of mutant SOD1 astrocytes on motor neurons. We find that this motor neuron toxicity involves both JNK and Bax. Thus, to further define the signaling pathways leading to motor neuron death triggered by mutant astrocytes, Specific Aim (SA)-I will: elucidate the MAPK core signaling module leading to JNK/Bax recruitment within motor neurons;characterize the functional link between JNK and Bax;and test the involvement of 14-3-3, p53 and Bim in the putative JNK/Bax interplay. The ability to generate large numbers of ES cell-derived motor neurons should facilitate the the proposed biochemical analyses. We find that the toxic activity is a polypeptide of ~5-15 kDa in size. Thus, to identify the toxic factor released by SOD1 mutant astrocytes, SA-II will: search for candidate toxic factors using both genomics and proteomics to compare wild- type and mutant astrocytes, and their conditioned media. Each candidate will be validated for toxicity and links to the JNK/Bax pathway. The role of non- neuronal cells in ALS remains unknown. Thus, to determine whether mutant astrocytes can affect the vitality of motor neurons in vivo, SA-III will: characterize the survival and development of mutant astrocytes grafted into the lumbar cord of wild-type rats of different ages;assess the number and morphology of neighboring wild-type motor neurons and inflammatory cells in response to mutant astrocyte grafts;and monitor the impact of mutant astrocyte grafts on motor function, axonal transport, and axonal dying back. This application contains a comprehensive set of experiments which should provide valuable insights into the cellular and molecular underpinning of mutant SOD1-mediated motor neuron degeneration. Information generated in this project should therefore have implications for the treatment and prevention of ALS.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is an incurable fatal paralytic disease in which inflammation is an increasingly recognized contributor to the disease process. We have found in a dish that specific inflammatory cells produce factors capable of killing the nerve cells responsible for ALS paralysis. Herein, we propose to;search for this toxic factor;to demonstrate by which mechanism it kills cells;and to demonstrate whether a similar situation occurs in an animal model of ALS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Gubitz, Amelie
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Columbia University (N.Y.)
Schools of Medicine
New York
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Le Masson, Gwendal; Przedborski, Serge; Abbott, L F (2014) A computational model of motor neuron degeneration. Neuron 83:975-88
Re, Diane B; Le Verche, Virginia; Yu, Changhao et al. (2014) Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 81:1001-8
Hirsch, Etienne C; Jenner, Peter; Przedborski, Serge (2013) Pathogenesis of Parkinson's disease. Mov Disord 28:24-30
de Vries, Rosa L A; Przedborski, Serge (2013) Mitophagy and Parkinson's disease: be eaten to stay healthy. Mol Cell Neurosci 55:37-43
Roybon, Laurent; Lamas, Nuno J; Garcia-Diaz, Alejandro et al. (2013) Human stem cell-derived spinal cord astrocytes with defined mature or reactive phenotypes. Cell Rep 4:1035-48
Phani, Sudarshan; Loike, John D; Przedborski, Serge (2012) Neurodegeneration and inflammation in Parkinson's disease. Parkinsonism Relat Disord 18 Suppl 1:S207-9
Gilkerson, Robert W; De Vries, Rosa L A; Lebot, Paul et al. (2012) Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition. Hum Mol Genet 21:978-90
Magrané, Jordi; Sahawneh, Mary Anne; Przedborski, Serge et al. (2012) Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci 32:229-42
Jackson-Lewis, Vernice; Blesa, Javier; Przedborski, Serge (2012) Animal models of Parkinson's disease. Parkinsonism Relat Disord 18 Suppl 1:S183-5
Becker, Dorothea; Richter, Judith; Tocilescu, Maja A et al. (2012) Pink1 kinase and its membrane potential (Deltaýý)-dependent cleavage product both localize to outer mitochondrial membrane by unique targeting mode. J Biol Chem 287:22969-87

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