|M.Sc Student||Harel Yafit|
|Subject||Interaction Between Cdk5 and Synphilin-1 Implications to|
the Pathogenesis of Parkinson's Disease
|Department||Department of Medicine||Supervisor||Professor Simone Engelender|
|Full Thesis text|
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. The pathological hallmarks of PD are the loss of dopaminergic neurons from the substantia nigra pars compacta in the midbrain and the presence of inclusions termed Lewy bodies (LBs). α-Synuclein is mutated in autosomal dominant PD and is also the major component of LBs in the sporadic form of the disease, supporting its general role in PD. Synphilin-1 interacts in vivo with α-synuclein and promotes the formation of cytoplasmic inclusions resembling LBs, emphasizing its importance in the pathogenesis of the disease. Ubiquitylation of synphilin-1 by E3 ubiquitin-ligase SIAH leads to its degradation by the proteasome. Furthermore, inhibition of proteasome function with accumulation of ubiquitylated synphilin-1 leads to the formation of LB-like inclusions. The role of synphilin-1 in cell survival is still controversial. Therefore, we sought to examine the effect of synphilin-1 on cell toxicity. We found that synphilin-1 protects against toxicity promoted by the dopaminergic toxin MPP and free radicals. Thus, our results clearly show that synphilin-1 has an important protective role against different toxins. Autophagy deficiency has been suggested to play a role in neurodegenerative diseases including PD. It is thought that autophagy can contribute to the clearance of cytosolic inclusions formed in the disease. We found that soluble synphilin-1 can increase the autophagic process, suggesting that the protective nature of synphilin-1 could be due to autophagic stimulation. Phosphorylation of proteins plays an important role in different neurodegenerative diseases, including PD. Cdk5 is elevated in dopaminergic neurons of PD brains and accumulates into LBs, suggesting its connection to PD. In an attempt to understand the mechanisms that regulate synphilin-1 activity, we sought to investigate additional effects of Cdk5 on synphilin-1 homeostasis as well as the effect of Cdk5 on synphilin-1 ability to protect against cell death. We obtained results showing that Cdk5 decreases synphilin-1 inclusion formation in cells, compatible with the decreased synphilin-1 ubiquitylation that was previously observed in our laboratory, which is in accordance with the general hypothesis that ubiquitylation of proteins are important for their inclusion formation. We also found that phosphorylation by Cdk5 decreases synphilin-1 ability to protect against toxicity. Understanding the relevance of Cdk5 and synphilin-1 interaction may help shed light on the molecular events that underlie PD.