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FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases
- Source :
- Journal of Neuroscience, J.Neurosci.
- Publication Year :
- 2009
-
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. Copyright © 2009 Society for Neuroscience. 29 25 8236 8247 Cited By :52
- Subjects :
- Cell Culture Techniques
nerve degeneration
Cell Count
Rats, Sprague-Dawley
Mice
androgen receptor
Excitatory Amino Acid Agonists
rat
Motor Neurons
Kainic Acid
Cell Death
General Neuroscience
Neurodegeneration
Forkhead Box Protein O3
article
transcription factor DAF 16
Forkhead Transcription Factors
Immunohistochemistry
medicine.anatomical_structure
Neuroprotective Agents
priority journal
Spinal Cord
motor neuron disease
transcription factor FKHRL1
Female
Drosophila
neuroprotection
Signal transduction
Neuron death
excitotoxicity
signal transduction
Signal Transduction
Programmed cell death
in vitro study
animal experiment
Blotting, Western
embryo
Biology
Neuroprotection
Article
Fluorescence
animal tissue
in vivo study
male
In vivo
medicine
Animals
controlled study
Motor Neuron Disease
protein expression
mouse
nonhuman
nerve cell necrosis
animal model
Computational Biology
Motor neuron
medicine.disease
Embryo, Mammalian
nuclear localization signal
Rats
Androgen receptor
Mice, Inbred C57BL
Disease Models, Animal
Tyrosine
Neuroscience
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Journal of Neuroscience, J.Neurosci.
- Accession number :
- edsair.doi.dedup.....25cf99c109bbe13b9202304279a28e3b