TY - JOUR
T1 - Protecting motor neurons from toxic insult by antagonism of adenosine A2a and Trk receptors
AU - Mojsilovic-Petrovic, Jelena
AU - Jeong, Goo Bo
AU - Crocker, Amanda
AU - Arneja, Amrita
AU - David, Samuel
AU - Russell, David
AU - Kalb, Robert G.
PY - 2006/9/6
Y1 - 2006/9/6
N2 - 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.
AB - 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.
KW - Adenosine A2a receptor
KW - Amyotrophic lateral sclerosis
KW - Brain-derived neurotrophic factor
KW - Motoneuron
KW - Transactivation
KW - Trk receptor
UR - http://www.scopus.com/inward/record.url?scp=33748497107&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33748497107&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1856-06.2006
DO - 10.1523/JNEUROSCI.1856-06.2006
M3 - Article
C2 - 16957081
AN - SCOPUS:33748497107
SN - 0270-6474
VL - 26
SP - 9250
EP - 9263
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 36
ER -