Vesicular recycling from the plasma membrane and disturbance of Ca2+ homeostase as determinants for alpha-synuclein induced cytotoxicity.

Parkinson's disease (PD) is the second most common neurodegenerative disorder in the Western world. Early studies mainly focused on the involvement of environmental factors in the development of PD. More recently, evidence is increasing that genetic factors also play a major role. The first gene identified to be associated with PD encodes for α-synuclein, an unfolded protein of 140 amino acids that is ubiquitously present in the brain. In addition, fibrillar α-synuclein was identified as the major protein component of Lewy bodies in the brain of sporadic PD patients. These findings emphasize α-synuclein as a major target in the research on the molecular mechanism underlying this complex disorder. Studies in different model organisms, including baker’s yeast, have revealed that the α-synuclein pathology is associated to failing protein quality control and clearance mechanisms, hampered vesicular trafficking, mitochondrial dysfunction and deregulation of intracellular Ca2+ signaling. Still many questions remain unsolved. In this project, we will use the so-called humanized yeast model to study in more detail the interaction of α-synuclein with vesicular trafficking. In a first part, we want to tackle the existing controversy about the localisation of the initial α-synuclein toxicity and correlate this to the phosphorylation status of the protein. In a second part, we mainly focus on the consequences of intracellular α-synuclein trafficking on Ca2+ signaling.