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The Journal of Neuroscience, June 24, 2009, 29(25):8236-8247; doi:10.1523/JNEUROSCI.1805-09.2009

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Neurobiology of Disease
FOXO3a Is Broadly Neuroprotective In Vitro and In Vivo against Insults Implicated in Motor Neuron Diseases

Jelena Mojsilovic-Petrovic,¹ Natalia Nedelsky,² Marco Boccitto,¹ Itzhak Mano,³ Savvas N. Georgiades,⁴ Weiguo Zhou,¹ Yuhong Liu,⁵ Rachael L. Neve,⁶ J. Paul Taylor,² Monica Driscoll,³ Jon Clardy,⁴ Diane Merry,⁵ and Robert G. Kalb^1,2

¹Department of Pediatrics, Division of Neurology, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, ²Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, ³Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers University, Piscataway, New Jersey 08854, ⁴Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, ⁵Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and ⁶Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02178

Correspondence should be addressed to Dr. Robert G. Kalb, Department of Pediatrics, Division of Neurology, Abramson Research Center, Children's Hospital of Philadelphia, 3416 Civic Center Boulevard, Philadelphia, PA 19104. Email: kalb{at}email.chop.edu

Aging is a risk factor for the development of adult-onset neurodegenerative diseases. Although some of the molecular pathways regulating longevity and stress resistance in lower organisms are defined (i.e., those activating the transcriptional regulators DAF-16 and HSF-1 in Caenorhabditis elegans), their relevance to mammals and disease susceptibility are unknown. We studied the signaling controlled by the mammalian homolog of DAF-16, FOXO3a, in model systems of motor neuron disease. Neuron death elicited in vitro by excitotoxic insult or the expression of mutant SOD1, mutant p150^glued, or polyQ-expanded androgen receptor was abrogated by expression of nuclear-targeted FOXO3a. We identify a compound [Psammaplysene A (PA)] that increases nuclear localization of FOXO3a in vitro and in vivo and show that PA also protects against these insults in vitro. Administration of PA to invertebrate model systems of neurodegeneration similarly blocked neuron death in a DAF-16/FOXO3a-dependent manner. These results indicate that activation of the DAF-16/FOXO3a pathway, genetically or pharmacologically, confers protection against the known causes of motor neuron diseases.

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Received April 15, 2009; revised May 20, 2009; accepted May 23, 2009.

Correspondence should be addressed to Dr. Robert G. Kalb, Department of Pediatrics, Division of Neurology, Abramson Research Center, Children's Hospital of Philadelphia, 3416 Civic Center Boulevard, Philadelphia, PA 19104. Email: kalb{at}email.chop.edu

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