S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by beta-amyloid peptide
Jing Qu1, Tomohiro Nakamura, Gang Cao
1Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Abstract:
The activity of Cdk5 and its regulatory subunit p35 is thought to be important in both normal brain function and neurodegenerative disease pathogenesis. Increased Cdk5 activity, via proteolytic cleavage of p35 to a p25 fragment by the calcium-activated protease calpain or by phosphorylation at Cdk5(Tyr15), can contribute to neurotoxicity. Nonetheless, our knowledge of regulation of Cdk5 activity in disease states is still emerging. Here we demonstrate that Cdk5 is activated by S-nitrosylation or reaction of nitric oxide (NO)-related species with the thiol groups of cysteine residues 83 and 157, to form SNO-Cdk5. We then show that S-nitrosylation of Cdk5 contributes to amyloid-β (Aβ) peptide-induced dendritic spine loss. Furthermore, we observed significant levels of SNO-Cdk5 in postmortem Alzheimer's disease (AD) but not in normal human brains. These findings suggest that S-nitrosylation of Cdk5 is an aberrant regulatory mechanism of enzyme activity that may contribute to the pathogenesis of AD.
Insights
Cyclin-dependent kinase 5 (Cdk5) activation by S-nitrosylation contributes to Alzheimer's disease (AD) pathogenesis. This aberrant enzyme activity, identified as SNO-Cdk5, is linked to amyloid-beta induced neuronal damage in AD brains.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Cyclin-dependent kinase 5 (Cdk5) and its regulatory subunit p35 are crucial for normal brain function.
- Dysregulated Cdk5 activity, through p35 cleavage or phosphorylation, contributes to neurotoxicity and neurodegenerative diseases.
Purpose of the Study:
- To investigate novel regulatory mechanisms of Cdk5 activity in the context of neurodegenerative diseases.
- To determine the role of nitric oxide (NO) related species in Cdk5 activation and its contribution to Alzheimer's disease (AD) pathogenesis.
Main Methods:
- Demonstrated Cdk5 activation via S-nitrosylation at cysteine residues 83 and 157 by NO-related species, forming SNO-Cdk5.
- Investigated the effect of S-nitrosylation on Cdk5 activity and its role in amyloid-beta (Aβ) peptide-induced dendritic spine loss.
- Analyzed postmortem human brain samples from Alzheimer's disease patients and normal controls for the presence of SNO-Cdk5.
Main Results:
- Cdk5 is activated by S-nitrosylation, forming SNO-Cdk5.
- S-nitrosylation of Cdk5 was shown to contribute to amyloid-beta induced dendritic spine loss.
- Elevated levels of SNO-Cdk5 were detected in postmortem Alzheimer's disease brains, but not in normal brains.
Conclusions:
- S-nitrosylation represents an aberrant mechanism for Cdk5 activation.
- Aberrant SNO-Cdk5 formation may play a significant role in the pathogenesis of Alzheimer's disease.
- Targeting S-nitrosylation could offer a novel therapeutic strategy for AD.
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