Fyn kinases play a critical role in neuronal apoptosis induced by oxygen and glucose deprivation or amyloid-β peptide treatment.
OBJECTIVE
Src family protein tyrosine kinases (SrcPTKs) have been implicated in the pathogenesis of brain ischemia and Alzheimer's disease (AD). In this study, we investigated whether Src and Fyn kinases, two major members of SrcPTKs in the brain, have distinct roles in the oxygen and glucose deprivation (OGD) and amyloid-β peptide (Aβ)-induced neuronal apoptosis.


RESULTS
The DAPI staining and caspase-3 activation analysis showed that small interfering RNAs (siRNAs) knockdown of Src or Fyn attenuated SH-SY5Y cells apoptosis after OGD and Aβ treatment. Fyn knockdown had a more potent neuroprotective effect than Src knockdown, suggesting a principal pathological significance of Fyn in brain ischemia and AD. Previously, we reported that brain ischemia promotes the phosphorylation of postsynaptic density protein 95 (PSD-95) at tyrosine 523 (Y523), which is associated with postsynaptic mechanisms of excitotoxicity. Here, immunoblot analysis indicated that not only OGD but also Aβ incubation increased the PSD-95Y523 phosphorylation. Src knockdown, especially Fyn knockdown, significantly inhibited such phosphorylation.


CONCLUSIONS
Fyn mediates PSD-95Y523 phosphorylation, which may be responsible for the excitotoxic signal cascades and neuronal apoptosis in brain ischemia and Aβ neurotoxicity. Fyn is a potential therapeutic target for the treatment of ischemic stroke and AD.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Jiangsu, China.
Cai-Ping
CP
Du
Ran
R
Tan
Xiao-Yu
XY
Hou
D016229:Amyloid beta-Peptides / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; C074636:amyloid beta-protein (25-35); D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D005947:Glucose