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Testing the ribosomal protein S6 as treatment target and biomarker in autism spectrum disorders

State/Province Full: 
United States

The diverse etiology of idiopathic autism spectrum disorders requires that efficient therapeutic treatment strategies, which are beneficial for a large subpopulation of patients, fulfill at least two criteria: (1) they should target neuronal dysfunctions present in many patients with different forms of autism, and (2) there should be measurable molecular or biochemical properties to identify individuals with autism that qualify for the specific treatment strategy and to quantitatively evaluate the efficacy of the treatment. The goal of this project is to provide initial support for a treatment target and strategy that could meet these criteria. Recent research has provided evidence that in many different forms of autism spectrum disorders, the molecular mechanisms regulating the production of proteins are defective. The tight regulation of protein production is essential for nerve cells to respond adequately to external stimuli and is thus fundamental for neurological function. Correcting defects in protein production is therefore a promising treatment strategy to potentially restore normal brain function. In particular, this study will examine a specific protein, the ribosomal protein S6, which is essential for the regulated production of proteins by using a drug to manipulate a protein, which ‘phosphorylates’ the ribosomal protein S6. S6 ‘phosphorylation’, a biochemical modification that can be measured quantitatively, is known to control the efficiency of S6 to regulate protein production. Analyses will show how the drug treatment affects neuronal function in a mouse model for fragile X syndrome, the most common monogenic form of autism. This approach will test the hypothesis that correcting S6 regulation may serve as a promising therapeutic strategy to ameliorate neurological dysfunctions in autism patients. Further analyses will determine if the drug affects S6 phosphorylation in immortalized peripheral blood cells from patients with idiopathic autism, and additional tests will determine if injection of living mice with the drug leads to changes in S6 phosphorylation in their blood cells. This would suggest that S6 phosphorylation could be used to assess the efficiency of a drug treatment, which will be important to evaluate the success of clinical studies with human patients. Taken together, this project has the potential to provide initial evidence that correcting defective S6 regulation may serve as a therapeutic target and biomarker for a subgroup of patients with autism.