Seung-Jae Lee (Korea, Republic of)
Seoul National University
Biomedical Sciences
Prof. Seung-Jae Lee is one of the leading scientists in the field of neurodegenerative diseases with special emphasis on Parkinson disease and related movement disorders and dementia. His research is centered around the role of protein aggregation in the pathogenesis of neurodegenerative diseases. He has been developing and analyzing the cellular and animal models of protein aggregation and studied basic principles of biological processes leading to protein aggregation and the clearance of the aggregates. Recently, his research is focused on the mechanism of progression of protein aggregate pathology and on the role of protein aggregates in neuroinflammation. His research now also includes the development of novel therapeutic drugs for Parkinson disease. Prof. Lee started his research group at the Parkinson’s Institute in Sunnyvale, CA in 2000, where he developed a research program for the study of pathophysiology of alpha-synuclein. He then moved to Konkuk University in Seoul, Korea in 2006, where he continued his work on alpha-synuclein and performed a series of studies on alpha-synuclein secretion and its roles in aggregate propagation and neuroinflammation. In 2015, Prof. Lee moved to Seoul National University in Seoul, Korea. While he continues the work on alpha-synuclein and Lewy body diseases, Dr. Lee is currently expanding the spectrum of his research program that now includes other neurodegenerative diseases-linked proteins, such tau, huntingtin, and TDP-43. Prof. Lee received undergraduate education at Seoul National University and graduate training at POSTECH. He performed postdoctoral works at National Institutes of Health in Bethesda, MD, and then at Harvard Medical School in Boston, MA. Prof. Lee has been an active member of several domestic and international scientific societies. He is currently serving as a senior editor of Brain Research and an associate editor for Experimental & Molecular Medicine.

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 Conference Calendar

PRE-RECORDED: INTERPLAY BETWEEN NEUROINFLAMMATION AND AGGREGATE PROPAGATION

Session Name
0750 - ALPHA-SYNUCLEIN AND DISEASE MECHANISMS (ID 38)
Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 114
Lecture Time
04:15 PM - 04:30 PM
Presenter

Abstract

Abstract Body

Cell-to-cell propagation of α-synuclein has been thought to be the underlying mechanism of progression of Parkinson’s disease. Recent evidence suggests that inflammation plays an important role in propagation of protein aggregates. However, the mechanism by which inflammation regulates aggregate propagation remains unknown. Here, we show that one of the pro-inflammatory cytokines, TNFα, promotes α-synuclein propagation through activating neuronal senescence. In an in vitro culture, factors secreted from activated microglia promotes cell-to-cell propagation of α-synuclein. Production of the propagation stimulator depended on AP-1 transcription factor. AP-1 target inflammatory factors were screened for propagation stimulating activity. We have identified both stimulatory and inhibitory factors, among which TNFα showed the most robust stimulatory activity. Transcriptome analysis in neurons exposed to TNFα showed that TNFα triggered cellular senescence, as well as immune responses and apoptotic processes. Experimentally, neurons showed senescent phenotypes upon exposure to TNFα. Interestingly, secretion of α-synuclein was increased in senescent neurons through the senescence associated secretory phenotype (SASP). Using vacuolin, an inhibitor of lysosomal exocytosis, and RNAi against rab27a, we demonstrated that the SASP was mediated by lysosomal exocytosis. Combined light and electron microscopy confirmed that propagating α-synuclein aggregates were present in electron-dense lysosome-like compartments. TNFα promoted the SASP through stimulating lysosomal exocytosis, thereby increasing the secretion of α-synuclein. Collectively, these results suggest that TNFα is one of the major inflammatory factors that drive cell-to-cell propagation of α-synuclein through stimulating SASP-mediated secretion of α-synuclein.

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