The role of alpha-synuclein in exocytosis under physiopathological scenarios in SH-SY5Y derived neural cells

• Grant number: 21/10654-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2021
• End date: November 30, 2022
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Merari de Fátima Ramires Ferrari
• Grantee: Lucas Calado de Almeida
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Alpha-synuclein is a 140-amino-acid protein coded by SNCA gene and is mainly found in presynaptic terminals of dopaminergic neurons, typically in a monomeric state. Structurally, the protein is divided into three domains: N-terminal, amphipathic; central domain (NAC), hydrophobic; lastly, C-terminal, the main target of post-translational modifications. In synucleinopathies, such as Parkinson's Disease and Lewy Body Dementia, alpha-synuclein is found in different oligomeric forms, assembling itself into cytotoxic inclusions, which are responsible for neuronal death and loss of psychomotor functions. Recently, alpha-synuclein has been associated with vesicle recycling processes, actively participating in SNARE complex assembly, crucial for neurotransmitter release. Taking into consideration the physiological condition, the protein seems to execute an anchoring role, where it binds to v-SNARE synaptobrevin II through the C-terminus and to the membrane through the N-terminus. Furthermore, the association of alpha-synuclein with membranes through its alpha-helices can lead to vesicle cluster formation in the cytosol, close to the membrane. Those vesicles are crucial for rapid neurotransmission when the action potential reaches the synaptic portion of the neuron. As a result, it is further suggested that the presence of clusters evidence that alpha-synuclein has a physiological role in vesicle recycling attenuation. In addition, some studies demonstrated that, pathologically, oligomeric alpha-synuclein selectively kidnaps SNARE complex proteins, decreasing their free-state concentration, affecting overall vesicular recycling processes. Yet, the dimension of alpha-synuclein's contribution to exocytosis and endocytosis processes in both physiological and pathological conditions remains elusive. Under the prism of neurodegeneration, a better understanding of alpha-synuclein's toxicity is paramount in order to come up with effective treatments for synucleinopathies. Nevertheless, it is also pivotal to comprehend the regulatory role of alpha-synuclein in vesicle recycling. Therefore, the present study aims to clarify the role of alpha-synuclein in vesicle recycling, with special attention to exocytosis. (AU)