FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases

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

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68 Scopus citations

Abstract

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 p150glued, 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.

Original languageEnglish (US)
Pages (from-to)8236-8247
Number of pages12
JournalJournal of Neuroscience
Volume29
Issue number25
DOIs
StatePublished - Jun 24 2009

ASJC Scopus subject areas

  • Neuroscience(all)

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    Mojsilovic-Petrovic, J., Nedelsky, N., Boccitto, M., Mano, I., Georgiades, S. N., Zhou, W., Liu, Y., Neve, R. L., Taylor, J. P., Driscoll, M., Clardy, J., Merry, D., & Kalb, R. G. (2009). FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases. Journal of Neuroscience, 29(25), 8236-8247. https://doi.org/10.1523/JNEUROSCI.1805-09.2009