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Identifier

000421836

Title

Study of pathology propagation mechanisms in neurodegenerative diseases

Alternative Title

Μελέτη μηχανισμών μετάδοσης παθολογίας σε νευροεκφυλιστικές νόσους

Author

Μαλάμη, Λήδα

Thesis advisor

Βεκρέλλης, Κώστας

Reviewer

Στεφανής, Λεωνίδας
Σπανάκη, Κλειώ

Abstract

Synucleinopathies are a group of neurodegenerative disorders in which the abnormal accumulation of insoluble α-synuclein fibrilar aggregates is shared as a basic trait and observed in the neurons and glial cells. Since α-synuclein is the main protein component of Lewy bodies, disorders that share the feature of LBs fall under the category of synucleinopathies. Α-synuclein is a small soluble protein of 140 amino acids which is primarily found in the presynaptic nerve terminals in the central nervous system. Subcellularly, the protein is sited in higher quantities at the presynaptic vesicles in the presynaptic nerve terminals without being engulfed in them. The Serine 129 (S129) phosphorylation of the protein is linked directly to the progress of PD. Regarding its degradation, it has been proposed that both the proteasome and the lysosome play a key role for α-synuclein. In general, the most accepted hypothesis of the pathological mode of action of α-synuclein is its ability to form oligomers and fibrils that can inhibit the proteasome and the lysosome, leading to further accumulation of the protein and induction of toxicity. It is widely accepted that a-synuclein is both physiologically and pathologically secreted and exerts its action on neighbouring cells, both neurons and glia following a pattern which agrees with the prion-like propagation model. Preliminary experiments in our lab, showed that the cytokine ActivinA was protective against the pathophysiology produced by pre-formed fibrils of α-synuclein (PFFs) in mice. To this end, we also wanted to investigate, whether such protection had an effect on behaviour and so male and female wild-type C57B16/C3H mice were used, which had been stereotactically injected with PFFs. The possible mechanism of ActivinA action was investigated in vitro using the SH-SY5Y human neuroblastoma cell line. Our results confirmed that PFF injections resulted in accumulation of phosphorylated α-synuclein in the cortex and striatum of the mice and that ActivinA treatment reduced this accumulation. The behavioural assays revealed impairments in the coordination and balance of the PFF mice linked to the phosphorylated α-synuclein aggregation. Some of these impairments were alleviated by ActivinA treatment revealing that histological reduction of phosphorylated α-synuclein is linked to improved behaviour. In vitro ActivinA failed to reduce the phosphorylated α-synuclein levels, or a reverse the proteasomal activity inhibition and had no effect on the lysosome.

Language

English

Subject

ActivinA

Synucleinopathies

a-synuclein

Συνουκλεϊνοπάθειες

α-συνουκλεϊνη

Issue date

2019-03-29

Collection

School/Department--School of Medicine--Department of Medicine--Post-graduate theses