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Cognitive impairment in Coffin-Lowry syndrome correlates with reduced RSK2 activation
K H Harum1, L Alemi, M V Johnston
1Kennedy Krieger Institute, Baltimore, MD, USA. Harum@kennedykrieger.org
Background:
Gene expression and protein synthesis, mediated by the transcription factor CREB (cAMP response element binding protein), play an important role in learning and memory in several species, including Drosophila, snails, and mice. Patients with the X-linked disorder Coffin-Lowry syndrome (CLS) have cognitive disabilities, distinctive features, and bony abnormalities as well as mutations in RSK2 (ribosomal S6 kinase-2), a protein kinase that activates CREB by phosphorylation at serine 133. In fibroblasts from a single patient with CLS, epidermal growth factor (EGF)-stimulated CREB phosphorylation was reduced.
Methods:
The authors assessed endogenous CREB phosphorylation in a CLS fibroblast line by Western blotting and found impaired CREB phosphorylation in response to stimulation by EGF and the protein kinase C (PKC) agonist phorbol 12-myristate 13-acetate (PMA). They studied RSK2 immunoprecipitated from fibroblasts and lymphoblasts from seven patients with CLS and found a wide range in RSK2's capacity to phosphorylate the synthetic CREB-like peptide, CREBtide, after cell stimulation by PMA.
Results:
In lymphoblasts from patients with CLS, PMA-stimulated CREBtide phosphorylation was increased 1.2- to 2.7-fold over baseline, compared to an average fourfold increase in controls. Regression analysis suggested a linear relationship between the magnitude of in vitro RSK2-mediated CREBtide phosphorylation and CLS patient intelligence level (p < 0.05).
Conclusions:
This report suggests a correlation between human cognitive performance and cellular capacity to activate RSK2. It provides additional evidence that the CREB kinase, RSK2, and CREB phosphorylation may play important roles in human learning and memory, as they do in lower animals.
Insights
Coffin-Lowry syndrome (CLS) involves mutations in RSK2, impairing cAMP response element binding protein (CREB) phosphorylation. This cellular defect correlates with cognitive performance in CLS patients, suggesting RSK2
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- cAMP response element binding protein (CREB) mediates gene expression and protein synthesis crucial for learning and memory.
- Coffin-Lowry syndrome (CLS), an X-linked disorder, is associated with mutations in ribosomal S6 kinase-2 (RSK2), a CREB-activating kinase.
- Reduced epidermal growth factor (EGF)-stimulated CREB phosphorylation was observed in fibroblasts from a CLS patient.
Purpose of the Study:
- To investigate endogenous CREB phosphorylation in CLS patient-derived cells.
- To assess the functional capacity of RSK2 in CLS patients.
- To explore the relationship between RSK2 activity and cognitive function in CLS.
Main Methods:
- Western blotting was used to assess CREB phosphorylation in CLS fibroblasts.
- RSK2 activity was studied by its capacity to phosphorylate a CREB-like peptide (CREBtide) in lymphoblasts from CLS patients.
- Stimulation was performed using EGF and phorbol 12-myristate 13-acetate (PMA).
Main Results:
- Impaired CREB phosphorylation was observed in response to EGF and PMA stimulation in CLS fibroblasts.
- PMA-stimulated CREBtide phosphorylation in CLS lymphoblasts showed a 1.2- to 2.7-fold increase over baseline, versus a fourfold increase in controls.
- Regression analysis indicated a linear relationship between in vitro RSK2-mediated CREBtide phosphorylation and CLS patient intelligence levels (p < 0.05).
Conclusions:
- A correlation exists between human cognitive performance and the cellular capacity to activate RSK2.
- These findings support the role of RSK2 and CREB phosphorylation in human learning and memory.
- The study provides further evidence for the conserved function of CREB in memory across species.