Title : Structure, Aggregation and Seeding Properties of Amyloid Proteins Associated with Neurodegenerative Diseases.
Speaker : Dr. Senthil Kumar Thangaraj, EPFL, Lausanne, Switzerland
Date : 11/11/2022, 05:30 PM , Classroom 1.
Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration (FTLD) are fatal but clinically distinctive disorders. These diseases, in common, are pathologically characterized by the presence of abnormal aggregation of one or many cellular proteins in different cell types, thus exhibiting different distributions of neurodegeneration. For example, TDP-43 in ALS/FTLD and a-synuclein in PD are the proteins that undergo aberrant aggregation. Enormous efforts have been underway to investigate the structure and formation of these pathological aggregates in vitro and in pre-clinical cellular models to understand the associated disease mechanisms and ultimately to develop novel strategies for diagnostic and therapeutic purposes. To gain insight into these, in my post-doctoral work, we worked on aims that employed multi-disciplinary approaches from structural biology to cell biology. In this presentation, I will talk about: 1) the knowledge that we gained on the sequence and structural determinants of TDP-43 aggregation and its proteolytic events that might lead to its neurotoxicity in ALS/FTLD1 ; 2) the efforts that we made for the development of the methods and tools for advancing research and drug discovery efforts in PD and other synucleinopathies2- 4 . Finally, I will also discuss how our current findings raise important questions that set the basis for my future research objectives.
1) Kumar ST, Nazarov S, Porta S, Maharjan N, Cendrowska U, Kabani M, Finamore F, Xu Y, Lee VMY, Lashuel HA. Unmasking the amyloid core of full-length TDP-43 filaments is a key determinant of their seeding activity (Revision in Nature Neuroscience).
2) Kumar ST, Mahul-Mellier AL, Hegde RN, Rivière G, Moons R, Ibáñez de Opakua A, Magalhães P, Rostami I, Donzelli S, Sobott F, Zweckstetter M, Lashuel HA. A NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity. Sci Adv. 2022 Apr 29;8(17):eabn0044.
3) Kumar ST, Jagannath S, Francois C, Vanderstichele H, Stoops E and Lashuel HA. How specific are the conformation-specific α-synuclein antibodies? Neurobiol Dis. 2020 Dec; 146:105086
4) Kumar ST, Donzelli S, Chiki A, Syed MMK and Lashuel HA. Towards improving experimental reproducibility in α-synuclein research. J Neurochem. 2020 Apr;153(1):103-119.