Defective phosphoinositide metabolism in autism.

Phosphoinositides are essential components of lipid membranes and crucial regulators of many cellular functions, including signal transduction, vesicle trafficking, membrane receptor localization and activity, and determination of membrane identity. These functions depend on the dynamic and highly regulated metabolism of phosphoinositides and require finely balanced activity of specific phosphoinositide kinases and phosphatases. There is increasing evidence from genetic and functional studies that these enzymes are often dysregulated or mutated in autism spectrum disorders; in particular, phosphoinositide 3-kinases and their regulatory subunits appear to be affected frequently. Examples of autism spectrum disorders with defective phosphoinositide metabolism are fragile X syndrome and autism disorders associated with mutations in the phosphoinositide 3-phosphatase tensin homolog deleted on chromosome 10 (PTEN), but recent genetic analyses also suggest that select nonsyndromic, idiopathic forms of autism may have altered activity of phosphoinositide kinases and phosphatases. Isoform-specific inhibitors for some of the phosphoinositide kinases have already been developed for cancer research and treatment, and a few are being evaluated for use in humans. Altogether, this offers exciting opportunities to explore altered phosphoinositide metabolism as a therapeutic target in individuals with certain forms of autism. This review summarizes genetic and functional studies identifying defects in phosphoinositide metabolism in autism and related disorders, describes published preclinical work targeting phosphoinositide 3-kinases in neurological diseases, and discusses the opportunities and challenges ahead to translate these findings from animal models and human cells into clinical application in humans. © 2016 Wiley Periodicals, Inc.