טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentShani Vered
SubjectStudy of LRRK2 in the Pathogenesis of Parkinson's Disease
DepartmentDepartment of Medicine
Supervisor Professor Simone Engelender


Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, it includes motor symptoms due to progressive degeneration of dopaminergic neurons and presence of Lewy bodies (LB) in the brain. LBs are cytoplasmic inclusions that contain several proteins, including ubiquitin and α-synuclein. Both α-synuclein and LRRK2 cause autosomal dominant forms of PD, they are considered as major proteins responsible for the disease.

The focus of our work was the study of LRRK2 and novel interactors. LRRK2 is a 280 KD protein that contains several domains; it is widely expressed throughout the brain and displays kinase activity against few identified substrates. The most prevalent LRRK2 mutation leads to a G2019S substitution, which is also consistently associated with sporadic cases of PD in different populations, Moreover, the G2019S mutation displays a higher LRRK2 kinase activity and induces neuronal degeneration, suggesting that changes in LRRK2 catalytic activities may lead to PD. LRRK2 is degraded by the proteasome. Since the proteasome activity was found decreased in sporadic forms of PD, it is possible that the accumulation of ubiquitinated LRRK2 could contribute to the formation of LRRK2 inclusions and perhaps LB.

We now show that the E3 ubiquitin-ligase SIAH interacts with LRRK2, promoting its ubiquitination, degradation and inclusion formation. We also show, for the first time, that LRRK2 is present in cells nucleus and that SIAH increases LRRK2 translocation to the nucleus. On the other hand, we also found that LRRK2 also increases SIAH translocation, suggesting that LRRK2 and SIAH may shift as a complex to the nucleus. Nevertheless, LRRK2 G2019S mutant was less efficient than the wild-type protein in promoting the translocation of SIAH to the nucleus, implying that perhaps the toxicity associated with G2019S may be due to its increased presence with SIAH in the cytosol.

In sum, we raise the possibility that LRRK2 may translocate to the nucleus together with SIAH. LRRK2 and SIAH complex presence in the nucleus represents now a novel targets to future PD treatment.