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Identifier

000451028

Title

The role of post-translational modifications on alpha-synuclein aggregation in neuronal cells

Alternative Title

Ο ρόλος των μεταμεταφραστικών τροποποιήσεων στη συσσωμάτωση της άλφα-συνουκλεϊνης σε νευρωνικά κύτταρα

Author

Γαβρά, Βασιλίνα-Ζαφείρα

Thesis advisor

Στεφανής, Λεωνίδας

Reviewer

Θερμού, Κυριακή
Ζαγανάς, Ιωάννης

Abstract

α-synuclein (α-Syn) is a small soluble presynaptic protein, physiologically associated with the recycling pool of synaptic vesicles, the regulation of neurotransmission and the stability of neuronal membranes. However, α-synuclein when misfolded or aggregated, can develop into cytoplasmic inclusions, also known as Lewy bodies, which are thought to be the main pathological feature in Parkinson’s disease (PD) and other related Synucleinopathies. A plethora of studies aims to unravel those processes that will eventually lead to the aggregation of α-Syn, including genetic factors, oxidative stress, and post-translational modifications (PTMs). α-Syn undergoes various post-translational modifications (PTMs), like phosphorylation, ubiquitylation, and SUMOylation, and there is an open question whether those PTMs have a positive or a negative effect on α-Syn aggregation and toxicity. The current study first aims to examine the effect of phosphorylation, Ubiquitylation, and SUMOylation on α-Syn aggregation propensity in primary cortical neurons and SHSY-5Y neuroblastoma cells, in the presence or absence of pre-formed fibrils (PFFs) of α-Syn. Secondly, we generated two new forms of α-Syn mutated at the lysine residues (K96, K102) which are the main sites of SUMOylation, in order to further investigate the role of SUMOylation on α-Syn pathology. Dissecting the involvement of different PTMs on α-Syn aggregation, could hopefully help to unravel the mechanisms underlying PD pathogenesis, and take us one step closer to develop potential therapies to treat PD. Highlights  Inhibition of the SUMOylation pathway induces α-Syn aggregation, resulting in α-Syn puncta increased in size, without affecting the levels of pS129 α-Syn aggregates.  Inhibition of the Ubiquitylation but not of the SUMOylation pathway, leads to the accumulation of pS129 α-Syn aggregates, with increased size.  The K96R α-Syn mutant seems to be more prone to aggregation than the WT protein.

Language

English

Subject

Parkinsons's disease

Protein aggregation

neurodegeneration

Νευροεκφύλιση

Νόσος πάρκινσον

Συσσωμάτωση πρωτεϊνών

Issue date

2021-07-29

Collection