Exploring the roles of PICK1 and ICA69 complex in diseases

Abstract

PICK1 (Protein Interacting with C-kinase 1) and ICA69 (Islet Cell Autoantigen 69kD) are BAR (Bin/Amphiphysin/Rvs) domain-containing proteins that tightly associate with each other in brain, pancreas and testis, and play crucial roles in AMPA receptor trafficking and vesicle transport. Male Pick1 knockout mice are completely infertile with a globozoospermia-like phenotype. Since PICK1 plays important roles in both hormone secretion and spermatogenesis, either deficit could lead to the impaired fertility. To distinguish these two possibilites, we restored PICK1’s expression specifically in the testis using seminiferous tubule microinjection of PICK1-containing lentiviruses. By examining the testis-specific Pick1 transgenic mice, we found that the re-expression of PICK1 in testis alone is sufficient to rescue the spermatogenic abnormalities and infertility in Pick1 knockout mice. Our results indicate that the infertility is caused by the lack of PICK1 in the testis rather than in other organs. In addition, we found that seminiferous tubule microinjection of lentivirus has a strong preference to produce testis-specific transgenic mice. Roles of PICK1-ICA69 complexes in diseases are not limited to infertility. Recently, several C-terminal truncation-related mutations of ICA69 were found in autism spectrum disorders (ASDs), but the mechanism is not clear. By investigating the function of ICAC (ICA69 C-terminus) domain, we found that ICAC not only could block the PDZ binding of PICK1, but also regulate the membrane association of PICK1 and ICA69 complexes. Therefore, with ICAC deficiency, the truncated mutant of ICA69 (ICAt) may retain PICK1’s PDZ-binding partners, such as GluR2 and neuroligins, together with the abnormal PICK1-ICAt complexes at the perinuclear region. In consequence, ICAt disrupts the trafficking of AMPA receptors and the maturation of neuroligins, thus impairing synaptogenesis and contributing to the development of ASD.

Date of Award	2013
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology