Characterization of lipid flip-flop induced by a-synuclein oligomers

INTRODUCTION

With the increase in lifespan of the population, neurodegenerative diseases caused by amyloid aggregates lead to dementia in an increasing number of patients. Among these diseases, one of the most prevalent is Parkinson’s disease (PD) which affects about 1 - 2 % of the population at an age above 65 years . The cause of the disease is a severe irreversible loss of neurons, which is accompanied by the formation of fibrillar cytoplasmic inclusions. However, the cellular mechanisms which lead to the neuronal loss are not understood in detail. While most cases of PD are sporadic, there are several known genetic factors associated with the disease. Among these, a key player is the protein α-synuclein. While α-synuclein fibrils presumably have only a mild effect on cell viability, oligomeric species are presumably highly toxic for the cells. While the exact mechanism by which these aggregated forms of the protein affect the neurons is still elusive, several in vivo and in vitro studies have shown that especially the oligomeric α-synuclein species lead to the permeabilization of both artificial and natural vesicular structures. Thus, they could interfere with many cellular pathways ranging from mitochondria to synaptic vesicles.

PROJECT DESCRIPTION

The exact mechanism by which the α-synuclein oligomers cause the permeabilization of membranes is still under dispute. Initial experiments suggest that apart from a pore-forming mechanism, α-synuclein oligomers could also affect phospholipid bilayers by an increase in lipid flip-flop. In vivo this could lead to the loss of the membrane asymmetry of cellular membranes, e.g. resulting in proapoptotic signals or the impairment of mitochondrial functions and eventually cell death.

In this BSc project you will measure the extent of lipid flip-flop caused by oligomeric α-synuclein species in model liposome systems, thereby identifying and characterizing important factors like degree of lipid order, membrane charge or the presence of monomeric α-synuclein. The results will help us to identify the underlying mechanism by which the noxious α-synuclein species presumably impair membrane function.

During the project you will:

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Learn how to prepare and purify α-synuclein oligomers.

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Learn how to prepare liposomes.

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Measure and analyse lipid flip-flop using fluorescence spectroscopy techniques.

MORE INFORMATION

If you are interested or would like more information, just contact me:

Dr. Martin Stöckl

Room: ZH 152 (Zuidhorst)

Phone: 053-4893161

Email: M.T.Stockl@utwente.nl