Monday, 2 December, 15h00 , MSG-025 Bernal Institute
Selective Brain Region Vulnerability in Parkinson’s Disease is Governed by α-Synuclein Conformations
Neuronal aggregates of alpha-synuclein (αSyn) (Lewy bodies and neurites) are a pathological hallmark of Dementia with Lewy Bodies (DLB) and Parkinson’s disease (PD). It has recently been discovered that αSyn, a neuronal protein of unclear physiological function, normally exists in cells and brain tissue principally as α-helically folded multimers that resist pathological aggregation. It can be shown that the helical form is not only resistant to time-dependent self-aggregation but also shows increased resistance (compared to unfolded monomers) to misfolding initiated by tiny amounts of fibrillar material, i.e., “seeded aggregation”. Based on new findings, it is important to identify factors that could trigger the denaturation of folded αSyn and allow its abnormal aggregation in neurons. It can be demonstrated that DLB and sPD patients exhibit a region-specific reduction of αSyn multimers in brain tissue according to the classical Braak staging scheme, indicating their destabilization in the course of the disease. The results indicate the vulnerability of early affected brain regions, the importance of a balance of αSyn multimers and monomers and the functional reserve of different brain regions. A factor governing the stabilization of multimers seems to be lipid composition of the cell specific membranes since transient lipid contact acts as a catalyst for multimer formation, meaning that lipid vesicles might act as a “liposomal chaperone” capable of conferring aggregation resistance to the large cytosolic pool of αSyn.
About the Presenter
Dr Tim Bartels is currently leading the program “Structure-Function Relationship in Neurodegeneration” at the UK Dementia Research Institute, University College London, in addition to his position as an Assistant Professor of Neurology at Brigham & Women’s Hospital and Harvard Medical School. He received his Master’s Degree in Chemistry at the Technical University Munich and conducted his PhD in Biophysics at the Adolf Butenandt Institute at the Ludwig-Maximilian University under the official supervision of Professor Johannes Buchner (Technical University Munich). He continued his post-doctoral training at Brigham & Women’s Hospital and Harvard Medical School where he also accepted his first faculty position as Instructor and later Assistant Professor of Neurology. His lab is dedicated to the involvement of the different forms of the presynaptic protein alpha-synuclein in Parkinson’s Disease and Dementia with Lewy Bodies. Furthermore, his lab is interested in novel context specific pathways of protein folding/misfolding and the involvement of lipids in neurodegeneration.