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Identifier

000362980

Title

Χρήση χημικών ουσιών που εμποδίζουν το σχηματισμό ολιγομερών της φυσιολογικά εκκρινόμενης α-συνουκλεϊνης. Επιπτώσεις στην κυτταροτοξικότητα

Alternative Title

Chemical compounds that prevent the formation of naturally secreted a-synuclein's oligomers. Effect on cytotoxicity

Author

Νικολάου, Καλλιόπη

Thesis advisor

Εμμανουηλίδου, Ευαγγελία
Βεκρέλλης, Κώστας

Reviewer

Στεφανής, Λεωνίδας
Ευθυμιόπουλος, Σ.
Θερμού, Κυριακή

Abstract

Alpha-synuclein is a 140 amino acid neuronal protein that has been associated with several neurodegenerative diseases. A point mutation in the gene coding for the a-synuclein protein was the first discovery linking this protein to a rare familial form of Parkinson’s disease. Subsequently, other mutations in the a-synuclein gene have been identified in familial Parkinson’s disease. The aggregated proteinaceous inclusions called Lewy bodies found in Parkinson’s disease and cortical Lewy body dementia were discovered to be predominantly a-synuclein. Aberrant aggregation of a-synuclein has been detected in an increasing number of neurodegenerative diseases, collectively known as synucleopathies. a-synuclein exists physiologically in both soluble and membrane-bound states, in unstructured and a-helical conformations, respectively. The physiological function of a-synuclein appears to require its translocation between these subcellular compartments and interconversion between the 2 conformations. a-synuclein’s propensity to oligomerize and form fibrils may be central to its toxicity. A precursor of those filamental structures, called protofibrils appears to be the most toxic formation. Thus, agents that block or prevent the formation of oligomers and/or fibrils might be neuroprotective. Already, several compounds have been tested for their ability to inhibit the assembly of a-synuclein into filaments in vitro. Biochemical analysis revealed the formation of soluble oligomeric a-synuclein in the presence of inhibitory compounds, suggesting that this may be the mechanism by which filament formation is inhibited. Unlike a-synuclein filaments and protofibrils, these soluble oligomeric species did not reduce the viability of cells. Until recently, a-synuclein was considered to exist as a conventional cytosolic protein. However, a series of new observations demonstrate the presence of a-synuclein in extracellular biological fluids, such as cerebrospinal fluid and plasma. The exact mechanism of this secretion has not been characterized. Thus, exocytosis of a-synuclein may be an important mechanism of amplifying and spreading degenerative changes from a small group of cells to its surrounding tissues, and it potentially provides therapeutic targets for halting the progression of the disease. In the present study we examine the possible cytotoxic effect of secreted a-synuclein species and the role of three inhibitory compounds: Congo red, Chrysamine G, Scyllo-inositol. These compounds have been used so far in studies with oligomeric aggregates of amyloid W peptide, which is responsible for cytotoxicity in Alzheimer’s disease and it has been found that they reduce or even inhibit Ab-induced toxicity. However, these compounds are themselves cytotoxic. Due to this, we performed a number of experiments in order to determine the ‘‘ideal’’ dose, and with this we mean the dose that has the most reducing result in aggregation and simultaneously the less toxic effect in cells’ survival. Our results showed that secreted a-synuclein species are cytotoxic. On the other hand, when the three compounds were added to conditioned medium, containing naturally secreted a-synuclein species, they produced a reduction in the cytotoxic effects caused by the application of this medium on differentiated neuroblastoma cells.

Language

Greek

Subject

A-Synuclein

Neurodegenerative Diseases

Oligomers

Secreted cytotoxicity

alpha-Synuclein

Α-Συνουκλεϊνη

Εκκρινόμενη κυτταροτοξικότητα

Ολιγομερή

Issue date