Study of the relation sequence-structure-toxicity of alpha-synuclein via a phylogenic approach
Objectives
The main objective of this project is to compare the sequence, structure and toxicity of the Parkinson-causing protein alpha-synuclein from humans and from a model of longevity (i.e the naked-mole rat). This project will provide new information on the biology of this protein and possible therapeutic strategies.
Abstract
Alpha-synuclein is a naturally disordered protein associated with Parkinson’s disease. However, little is known about its biology and how it becomes toxic for neurons. Studies have focused mostly on the human sequence by exploring the role of mutations found in patients or by examining the consequence random mutagenesis. The naked mole rat is model of longevity that carries a unique sequence of alpha-synuclein. We hypothesize that a comparative phylogenic approach can provide important information on the biology of this protein. The relation sequence-structure-function will be studied using complementary approaches ranging from biophysical analysis (in collaboration with Dr. Vincent Forge, CEA Grenoble and Dr. Kevin Pounot, Tubingen University) to the analysis of aggregation and toxicity in vitro (yeast and primary neuronal cultures) and in vivo (mice). These aspects will be examined using recombinant proteins and viral vectors (lentiviral and AAV). The student will learn many cutting-edge techniques.
Methods
The project includes the following methods: structural analysis (atomic force microscopy, circular dichroism), protein production, aggregation kinetic, toxicity study in yeast, neuronal cultures and mice; histology, confocal microscopy, western blot, FACS, stereotaxic surgery, viral vectors.
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