Targeting the Pigment Epithelium-Derived Factor (PEDF) Signaling Pathway in Neurodevelopmental Disorders - PROJECT SUMMARY The prevalence of autism spectrum disorder (ASD) in the United States is 1 in 44 in children, with more than 5 million adult Americans and about 1% (more than 75 million people) of the world population having ASD. ASD is characterized by four core symptoms, which are; impaired communication and social interaction, restrictive interests, repetitive behaviors, and irritability. Current medications are limited and focus only on irritability, which is just one of the four core symptoms. To relieve the severe burden of this disease, the development of novel medications that can address the full range of ASD behaviors is an urgent unmet need. Defects in neuronal morphogenesis, including neurite formation, spine formation and synaptogenesis, cause improper neural connectivity, which has been implicated in neurodevelopmental disorders, such as ASD, epilepsy, and mental retardation. Recent studies have shown that many ASD animal models and human models using induced pluripotent stem cells (iPSCs) show decreased neurite length. We have recently found that Pigment Epithelium- Derived Factor (PEDF) plays a critical role in neuronal morphogenesis and neural activity in vivo, including neurite formation, spine formation and calcium signaling. Preliminary data show that the treatment of primary cortical neurons with PEDF-derived snippet, called PEDF(44-mer) (amino acid 78-121) peptide accelerates neurite formation. Also, we found that PEDF(44-mer) could rescue social interaction defects in prenatal valproic acid (VPA)-exposed mice. In addition, our proteomic analysis revealed the activity-dependent neuroprotective protein (Adnp) is a potential downstream effector of PEDF signaling pathway. ADNP mutations in humans are among the most common single-gene causes of ASD and result in ADNP syndrome. We found that PEDF(44- mer) could rescue social interaction defects and repetitive behavior seen in the Adnp+/- mice. Therefore, in Aim 1, we will investigate whether treatment of the Adnp+/- mice with PEDF peptides can ameliorate the defects in neuronal morphogenesis, including neurite formation and spine formation. In Aim 2, we will test whether PEDF peptides can ameliorate the defects in synapse formation and neural connectivity seen in the Adnp+/- mice. Since our proposal will test a potential new medication target for the defects in early developmental stages seen in children with ADNP syndrome and ASD, our study makes a major contribution to a field that would benefit millions of people in the United States. We will scrutinize the possibility of a novel drug useful for treating the impairment of neuromorphogenesis and neural connectivity during early development, which are incurable with existing medications. Thus, the successful completion of the research will lead to the improvement of the quality of life of children and adults with ASD and neurodevelopmental disorders.
