Speakers

Mechanism of disease progression in Parkinson’s disease

이승재
Seung-Jae Lee
Seoul National University
Nov. 30 15:15~15:45

Abstract

Synucleinopathies are neurological disorders, characterized by neuronal and glial deposition of a-synuclein aggregates. These disorders include Parkinson’s disease (PD), dementi with Lewy bodies, and multiple system atrophy. Cell-to-cell transmission of these aggregates are thought to be the underlying mechanism of aggregate spreading in patients’ brain and perhaps of clinical progression. Interfering with the aggregate transmission can thus be a potential strategy for halting the disease progression. However, the mechanism by which α-synuclein aggregates spread remains undefined. Here, I present the evidence that α-synuclein aggregates are perpetually transmitted through a continuous cycle involving uptake of external aggregates, co-aggregation with endogenous α-synuclein, and exocytosis of the co-aggregates. Moreover, we found that glucocerebrosidase 1 depletion, which has previously been strongly associated with PD and increased cognitive impairment, promoted propagation of α-synuclein aggregates. Depletion of other genes such as ctsd (cathepsin D) resulted in lysosomal dysfunctions and further confirmed that lysosomal dysfunction is the key modulator of spreading of synucleinopathy. These studies define how α-synuclein aggregates spread among neuronal cells and explain how lysosomal dysfunction increase the risk of developing PD and other synucleinopathies. Another important issue regarding the aggregate propagation is the identification of receptors that mediate the propagation process. Recently, my lab identified toll-like receptor 2 (TLR2), an innate immune receptor, as the receptor for neuron-released a-synuclein oligomers in microglia. I will show evidence that TLR2 plays an important role in cell-to-cell transmission of a-synuclein aggregates, regulating both secretion and uptake of the aggregates. Furthermore, administration of a neutralizing antibody for TLR2 interferes with the intercellular transmission of a-synuclein and thus, alleviates synucleinopathy lesions and neuroinflammation. I propose the anti-TLR2 treatment as a therapeutic strategy for Parkinson’s disease and related synucleinopathies.

 

Education

  • 1992-1995, Ph.D, Department of Life Science, Pohang University of Science and Technology, Pohang, Korea
  • 1990-1992, M.S., Department of Life Science, Pohang University of Science and Technology, Pohang, Korea
  • 1985-1989, B.S., Department of Biology Education, Seoul National University

 

Professional Career

  • 2015-, Professor, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
  • 2011-2015, Professor, Department of Biomedical Science and Technology, Konkuk University, Seoul, Korea
  • 2006-2011, Associate Professor, Department of Biomedical Science and Technology, Konkuk University, Seoul, Korea
  • 2000-2006, Assistant Professor, The Parkinson’s Institute, Sunnyvale, CA
  • 1998-2000, Instructor in Neurology, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA
  • 1996-1998, Postdoctoral Fellow, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA
  • 1995-1996, Postdoctoral Fellow, Laboratory of Molecular Cardiology, NHLBI, NIH, Bethesda, MD

 

Awards and Honors

  • 2016, Research Excellence Award, Seoul National University College of Medicine
  • 2013, Research Grand Prize, Konkuk University
  • 2013, Killam Lecture, Montreal Neurological Institute, McGill University
  • 2012, 2014 Excellent paper award in science and technology (The Korean Federation of Science and Technology Societies)
  • 2010, 2014 Excellence in Basic Research (Ministry of Education, Science, and Technology)
  • 2000, International Parkinson’s Research Award (Parkinson’s disease foundation)
  • 1995-1997, NIH Postdoctoral Fellowship from Fogarty International Center