Unraveling the role of A-synuclein phosphorylation in the etiology of parkinson's disease

Abstract

Event Abstract Back to Event Unraveling the role of A-synuclein phosphorylation in the etiology of parkinson's disease Olga Sin1*, Sandra Tenreiro1 and Tiago Fleming-Outeiro1, 2 1 Instituto de Medicina Molecular, Cell and Molecular Neuroscience Unit, Portugal 2 Faculdade de Ciências da Universidade do Porto, Instituto de Fisiologia, Portugal Alpha-synuclein (aSyn) is a cytosolic protein of unknown function predominantly expressed in the brain and is associated with a set of neurodegenerative disorders commonly known as synucleinopathies. These include Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. In addition to the loss of dopaminergic neurons in the brain of PD patients, another neuropathological feature is the presence of Lewy Bodies (LB) that consist of intraneuronal protein aggregates composed of misfolded proteins. aSyn is the major component of LBs, which also include ubiquitin, molecular chaperones, and proteasome subunits. Immunohistochemical labeling has shown that, in LBs, aSyn is extensively phosphorylated at Serine 129. Given that in the normal human brain phosphorylated aSyn is rare, investigating how phosphorylation of this protein contributes to the diseased brain may give more insight into the pathogenesis of PD. The budding yeast Saccharomyces cerevisiae is a valuable tool for the study of neurodegenerative diseases such as Alzheimer’s or Huntington’s disease and, most importantly, in the case of PD, it has already been shown that aSyn induces cytotoxicity in a concentration-dependent manner and that this reflects in inclusion formation in yeast cells, mimicking what is observed in the brain of PD patients [1]. Therefore, we are using the yeast cell to study a selection of brain specific kinases known to regulate aSyn phosphorylation and assess for parameters that include aSyn toxicity, inclusion formation and vesicle trafficking. These findings will enable us to better understand the molecular and cellular mechanisms underlying PD and, consequently, will provide tools for the development of novel therapeutic strategies.