Consequences of TG2-mediated post-translational modifications on ?-synuclein oligomer and fibril formation pathways. Grant uri icon

abstract

  • A hallmark of Parkinson?s disease is the initial development of protein aggregates enriched with the intrinsically disordered protein, a-synuclein, in the brain. As a-synuclein aggregation progresses, toxic protein plaques within neurons quickly lead to cell death, resulting in cognitive and mental decline. The process of aggregation is thought to occur through a step-wise and progressive mechanism beginning with an initial nucleation event followed by the formation of various intermediate oligomeric species. As the toxic oligomeric species increase in numbers, they combine to form fibrillar-amyloid species comprised of a-synuclein in a rigid ?-conformation. Little, however, is currently known as to how this natively disordered protein is able to adopt and maintain the highly structured and organized oligomeric and amyloid-fibril species characteristic of the protein aggregates in the early stages of the disease. In fact, the conformational plasticity of a-synuclein is key to its physiological role in the brain and the protein can adopt multiple, aggregate-resistant conformations. From the perspective of understanding the molecular mechanisms of a-synuclein oligomerization and fibrillization pathways, the challenge is to identify not only what conformations of a-synuclein are aggregate-competent but also why they promote aggregation. For example, post-translation modifications (PTMs) of a-synuclein are thought to stabilize toxic conformations. Specifically, TG2 mediated PTM of a-synuclein, including polyamidation, covalent cross-linking and phosphorylation, substantially increases a-synuclein oligomer and fibril formation in vitro. Post-mortem brain tissue analysis also shows that protein plaques and Lewey bodies contain a substantial amount of TG2-modified a-synuclein. While TG2-mediated modifications are correlated with increased a-synuclein aggregation, the molecular consequences of these PTMs on the biochemical, structural, and aggregation properties of a-synuclein are unclear, leading to a fundamental gap in knowledge regarding why these specific PTMs cause a-synuclein to adopt aggregation-competent conformations. In light of our preliminary data, which shows that TG2 can post-translationally modify a-synuclein under physiological conditions (i.e. low ca/high GTP), identification of the molecular mechanisms behind TG2-mediated a-synuclein aggregation could yield novel and more tractable therapeutic targets to treat PD and related synucleinopathies from the standpoint of developing therapeutic interventions preventing a-synuclein from adopting these aggregate-prone conformations.

date/time interval

  • September 2017 - December 2018