Increased expression of a proline-rich Akt substrate (PRAS40) in human copper/zinc-superoxide dismutase transgenic rats protects motor neurons from death after spinal cord injury

J Cereb Blood Flow Metab. 2008 Jan;28(1):44-52. doi: 10.1038/sj.jcbfm.9600501. Epub 2007 Apr 25.


The serine-threonine kinase, Akt, plays an important role in the cell survival signaling pathway. A proline-rich Akt substrate, PRAS40, has been characterized, and an increase in phospho-PRAS40 (pPRAS40) is neuroprotective after transient focal cerebral ischemia. However, the involvement of PRAS40 in the cell death/survival pathway after spinal cord injury (SCI) is unclear. Liposome-mediated PRAS40 transfection was performed to study whether overexpression of pPRAS40 is neuroprotective. We further examined the expression of pPRAS40 after SCI by immunohistochemistry and Western blot using copper/zinc-superoxide dismutase (SOD1) transgenic (Tg) rats and wild-type (Wt) littermates. We then examined the relationship between PRAS40 and Akt by injection of LY294002, a phosphatidylinositol 3-kinase (PI3K) pathway inhibitor, or Akt inhibitor IV, a compound that inhibits Akt activation after SCI. Our data demonstrated that increased pPRAS40 resulted in survival of more motor neurons compared with control complementary DNA transfection. Phosphorylated PRAS40 increased in the Wt rats after SCI, whereas there was a greater and prolonged increase in the SOD1 Tg rats. Coimmunoprecipitation showed that binding of pPRAS40 with 14-3-3 increased 1 day after SCI in the Wt rats, whereas there was a significant increase in the Tg rats. The inhibitor studies showed that phospho-Akt and pPRAS40 were decreased after injection of LY294002 or Akt inhibitor IV. We conclude that an increase in pPRAS40 by transfection after SCI results in survival of motor neurons, and overexpression of SOD1 in the Tg rats results in an increase in endogenous pPRAS40 and a decrease in motor neuron death through the PI3K/Akt pathway.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Animals, Genetically Modified
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Cell Death / drug effects
  • Cell Death / genetics
  • Chromones / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Enzyme Inhibitors / pharmacology
  • Gene Expression
  • Humans
  • Morpholines / pharmacology
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Neuroprotective Agents / metabolism*
  • Phosphatidylinositol 3-Kinases / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins / biosynthesis*
  • Phosphoproteins / genetics
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Spinal Cord Injuries / genetics
  • Spinal Cord Injuries / metabolism*
  • Spinal Cord Injuries / pathology
  • Superoxide Dismutase / biosynthesis*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1
  • Time Factors
  • Transfection
  • Transgenes


  • Adaptor Proteins, Signal Transducing
  • Akt1s1 protein, rat
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Neuroprotective Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • SOD1 protein, human
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Sod1 protein, rat
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Proto-Oncogene Proteins c-akt