FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases.
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.
Mojsilovic-Petrovic
Jelena
J
Department of Pediatrics, Division of Neurology, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Nedelsky
Natalia
N
Boccitto
Marco
M
Mano
Itzhak
I
Georgiades
Savvas N
SN
Zhou
Weiguo
W
Liu
Yuhong
Y
Neve
Rachael L
RL
Taylor
J Paul
JP
Driscoll
Monica
M
Clardy
Jon
J
Merry
Diane
D
Kalb
Robert G
RG
D000818:Animals; D015153:Blotting, Western; D002452:Cell Count / Q000379:methods; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D019295:Computational Biology; D004195:Disease Models, Animal; D004330:Drosophila; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D005453:Fluorescence; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D018696:Neuroprotective Agents; C501142:psammaplysene A; D014443:Tyrosine; D007608:Kainic Acid