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FOXO3 protects motor neurons

FOXO3 protects motor neurons - 8236 The Journal of...

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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 1 Department of Pediatrics, Division of Neurology, Abramson Research Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, 2 Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, 3 Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers University, Piscataway, New Jersey 08854, 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, 5 Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and 6 Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02178 Aging is a risk factor for the development of adult-onset neurodegenerative diseases. Although some of the molecular pathways regulat- ing 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 neurodegen- eration 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. Introduction Although motor neuron diseases attributable to single gene mu- tations are unusual ( 10% of cases), the affected genes have been successfully used to model these diseases in experimental systems (Cleveland and Rothstein, 2001). Rare, genetic forms of motor neuron disease that arise from mutations in superoxide dis- mutase (SOD) or p150 glued have a disease phenotype that strongly resembles sporadic amyotrophic lateral sclerosis (ALS) with lower motor neuron predominance (Pasinelli and Brown, 2006). Another predominantly lower motor neuron disease, called spinobulbar muscular atrophy (SBMA) (or Kennedy’s dis- ease) is attributable to a polyglutamine expansion in the andro- gen receptor (AR) (La Spada et al., 1991). Despite identification of the “disease protein,” the underlying pathogenic mecha- nism(s) remain incompletely understood.
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