טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKemeny Stav
SubjectInvolvement of the Pro-Apoptotic Protein ARTS in Parkinson's
Disease: Parkin is an E3-Ligase for ARTS
DepartmentDepartment of Medicine
Supervisors Professor Emeritus John Finberg
Ms. Sarit Larisch
Full Thesis textFull thesis text - English Version


Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by selective degeneration of the dopaminergic neurons in the substantia nigra.

A variety of evidence has supported an apoptotic contribution to neuronal loss in PD. Septins were found to have important roles in neuropathobiology.  Taking into consideration that ARTS protein is a Septin family member and a potent pro-apoptotic protein, I aimed at investigating the potential role of ARTS in PD. ARTS is localized to the mitochondria and promotes apoptosis through direct binding to XIAP, a member of the IAP-family of apoptosis inhibiting proteins. Binding of ARTS to XIAP causes a significant reduction in XIAP levels, leading to caspase activation and apoptosis. Examining human post mortem brain samples for ARTS protein expression, I revealed that ARTS is highly expressed throughout the normal brain but its levels are significantly lower in striatum of PD brain. To learn about the role of ARTS in human neurons, the SH-SY5Y brain-derived neuroblastoma cell line was used as a model for dopaminergic neurons. Endogenous ARTS in SH-SY5Y neuronal cells exhibits similar features to those of ARTS in non-neuronal cells. It was previously shown that in healthy cells ARTS levels are kept low through degradation by the ubiquitin-proteasome system (UPS). The UPS has been implicated in the regulation of apoptosis. Furthermore, defects in the UPS have been implicated in neurodegenerative disorders such as PD. Mutations in Parkin, a RING E3 ubiquitin ligase, appear to be the most frequent cause of familial PD. Here, I show that Parkin serves as an E3 ligase for ARTS and inhibits ARTS-induced apoptosis, thereby indicating a possible role for ARTS in PD. XIAP serves as an E3 ligase for ARTS as well. I found that XIAP and Parkin bind and regulate each other. ARTS, presumably acting as a scaffold, could bring Parkin and XIAP into proximity where they probably ubiquitinate each other. This leads to the reduction in XIAP protein cellular levels in a proteasome-dependent manner and to ubiquitination of Parkin by XIAP, possibly for signaling purposes.  ARTS, Parkin and XIAP are partners in a complex in which mutual modulation controls apoptosis regulation. I propose that in Parkinson’s disease patients, where Parkin loses its E3 ligase activity, ARTS levels are up-regulated and uncontrolled apoptosis occurs.