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The Journal of Neuroscience, September 6, 2006, 26(36):9250-9263; doi:10.1523/JNEUROSCI.1856-06.2006

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Neurobiology of Disease
Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

Jelena Mojsilovic-Petrovic,¹ Goo-Bo Jeong,^1,2 Amanda Crocker,¹ Amrita Arneja,¹ Samuel David,¹ David Russell,³ and Robert G. Kalb¹

¹Department of Neurology, Children’s Hospital of Philadelphia, Joseph Stokes Jr. Research Institute, Philadelphia, Pennsylvania 19104, ²Department of Anatomy, College of Medicine, Chungbuk National University, Cheong-ju 361-763, Republic of Korea, and ³Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06519

Correspondence should be addressed to Robert G. Kalb, Children’s Hospital of Philadelphia/Abramson Research Center #814, 3615 Civic Center Boulevard, Philadelphia, PA 19104. Email: Kalb{at}email.chop.edu

The death of motor neurons in amyotrophic lateral sclerosis (ALS) is thought to result from the interaction of a variety of factors including excitotoxicity, accumulation of toxic proteins, and abnormal axonal transport. Previously, we found that the susceptibility of motor neurons to excitotoxic insults can be limited by inhibiting signals evoked by brain-derived neurotrophic factor (BDNF) activation of the receptor tyrosine kinase B (TrkB). Here we show that this can be achieved by direct kinase inhibition or by blockade of a transactivation pathway that uses adenosine A2a receptors and src-family kinases (SFKs). Downstream signaling cascades (such as mitogen-activated protein kinase and phosphatidylinositol-3 kinase) are inhibited by these blockers. In addition to protecting motor neurons from excitotoxic insult, these agents also prevent toxicity that follows from the expression of mutant proteins (G85R superoxide dismutase 1; G59S p150^glued) that cause familial motor neuron disease. TrkB, adenosine A2a receptors, and SFKs associate into complexes in lipid raft and nonlipid raft membranes and the signaling from lipids rafts may be particularly important because their disruption by cholesterol depletion blocks the ability of BDNF to render motor neurons vulnerable to insult. The neuroprotective versatility of Trk antagonism suggests that it may have broad utility in the treatment of ALS patients.

Key words: adenosine A2a receptor; brain-derived neurotrophic factor; Trk receptor; transactivation; amyotrophic lateral sclerosis; motoneuron

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Received Dec. 6, 2005; revised Aug. 4, 2006; accepted Aug. 4, 2006.

Correspondence should be addressed to Robert G. Kalb, Children’s Hospital of Philadelphia/Abramson Research Center #814, 3615 Civic Center Boulevard, Philadelphia, PA 19104. Email: Kalb{at}email.chop.edu

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