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Identifier

000370737

Title

Ολιγομερισμός της πρωτεϊνης LRRK2 στη νόσο Parkinson

Alternative Title

LRRK2 oligomerization in Parkinson's disease.

Author

Βαλκιμάδη Πολυτίμη-Ελένη

Thesis advisor

Στεφανής, Λ.

Reviewer

Πλαϊτάκης, Α.
Rideout H

Abstract

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder of unknown etiology that mainly affects motor functions and it is pathologically characterized by the selective loss of dopaminergic neurons in the substantia nigra and aggregated protein deposits called Lewy bodies. Mutations in the gene encoding LRRK2 account for the majority of familial cases and for a significant percentage of sporadic cases as well. LRRK2 is a large, multi-domain protein that consists of protein-protein interaction domains, surrounding a central enzymatic core. The pathogenic mutations are located in the enzymatic regions. The precise mechanism by which mutations in LRRK2 induce neuronal death is not yet understood, however it is known that mutant LRRK2 increases its association with the apoptotic proteins FADD and caspase-8. There also some indications that LRRK2 has the property of oligomerization, a property shared by other protein families, especially those implicated in the apoptotic signaling pathways. In addition, it was known that caspase-8 cleaves RIP1at a specific motif, when cells undergo TNF-α induced apoptosis. This same motif was found to be present in LRRK2. The proposed model predicts that the pathogenic mutations cause an initial oligomerization, which is responsible for the enhanced association of LRRK2-FADD. It was also hypothesized that caspase-8 cleaves LRRK2 in the same motif facilitating the pre-apoptotic role of mutant LRRK2. The aim of this study is to further investigate this property of oligomerization and to assess the impact of mutant LRRK2 on this phenomenon as well as the biochemical profile of these potentially oligomeric conformations. It is also attempting to assess the influence on 6 oligomerization, if there is any, of a second, artificial mutation (D1565K) that removes the caspase-8 cleavage site. It was found that mutant LRRK2 causes increased formation of cytoplasmic, filamentous structures compared to the wild type, which represent higher-order complexes and that D1565K mutation ameliorates this phenotype. It is, therefore, possible that LRRK2 oligomerization may be a critical step in neuronal death induction. However, in order to identify the underlying mechanism of neurodegenaration, it is necessary to link these findings with toxic effects and neuronal death.

Language

Greek

Subject

Filaments nerotoxicity

Nervous system

Oligomerization

Parkinson's disease

Protein

Νευροτοξικότητα

Νόσος Πάρκινσον

Ολιγομερισμός

Πρωτεϊνη