The Role of Phosphorylation and Oligomerixation on Alpha-synuclein-induced Vesicle Rupture
Rapid Response Innovation Awards, 2013
Objective/Rationale: † † † † † ††
The propagation of pathological alpha-synuclein in the central nervous system resembles a spreading viral infection. We have observed that alpha-synuclein can enter neurons by inducing the rupture of endocytic vesicles in a manner that is very similar to what is induced by many viruses. This study will establish if phosphorylation (addition of a phosphate group) or familial mutations of alpha-synuclein convey an increased ability to enter cells in this way, thus increasing the pathological potential of these forms of alpha-synuclein.
Project Description: † † † † † ††
In this study, we will generate alpha-synuclein aggregates in vitro using typical alpha-synuclein, phosphorylated alpha-synuclein and alpha-synuclein harboring mutations associated with familial PD. Using these aggregates, we will assess their ability to induce the rupture of endocytic vesicles. We will also examine how vesicle rupture by these forms of alpha-synuclein induces mitochondrial stress by releasing digestive enzymes (called cathepsins) from these endocytic vesicles.
Relevance to Diagnosis/Treatment of Parkinsonís Disease: † † † † † † † † † ††
We hypothesize that the stress induced by vesicle rupture will lead to the spread of alpha-synuclein between cells during the progression of Parkinsonís disease. Understanding how vesicle rupture governs the spread of alpha-synuclein pathology may reveal new targets to halt the development of symptoms that arise from neuronal death and dysfunction in Parkinsonís disease patients.†
Anticipated Outcome: † † † † †
It is well established that certain mutations in alpha-synuclein induce an early onset, familial form of Parkinsonís disease. Similarly, pathological forms of alpha-synuclein are known to be phosphorylated on a specific residue of the alpha-synuclein protein. This study will determine how these changes correlate with the ability of alpha-synuclein to induce vesicle rupture and cellular stress, which will provide critical insight into the molecular mechanisms underlying the pathological spread of alpha-synuclein in Parkinsonís disease.†
Associate Professor at Stritch School of Medicine, Loyola University Chicago
Location: Maywood, Illinois, United States