Identification of novel proteins regulating pael-receptor function

Abstract

Parkinson's disease (PD) is a chronic neurodegenerative disorder that causes a wide range of debilitating symptoms. The Parkin associated endothelin like receptor (PAEL-R), originally called GRP37, belongs to the family of orphan G coupled protein receptors (GPCRs). Under physiological conditions the E3 ligase, called parkin, ubiquitinates the unfolded PAEL-R to promote its degradation. When parkin is mutated in PD the PAEL-R aggregated in the endoplasmic reticulum (ER) inducing ER stress, which leads to neurotoxicity and cell death (Chapter 1). The aim of our project was to discover interacting proteins which control the trafficking and expression of PAEL-R. To study these mechanisms of PAEL-R, we have identified novel proteins that interact with these receptors using a yeast-two hybrid genome-wide technology and further validate these findings by biochemical and cellular studies. Results reveal three novel proteins interacting with the PAEL-R. These are (1) protein interacting with C kinase (PICK 1) (Chapter 3), (2) y-aminobutyrate type A receptor associated protein like 2 (GABARAPL2) (Chapter 4) and (3) ras-associated binding protein 14 (Rab14) (Chapter 5). Based on these novel findings we hope to better understand PAEL-R aggregation and trafficking for the treatment of PD.