HYBRID EVENT: You can participate in person at Rome, Italy or Virtually from your home or work.
Speaker at International Alzheimer’s Disease & Dementia Conference 2022 - Xiaobo Mao
Johns Hopkins School of Medicine, United States
Title : Pathogenic ?-synuclein cell-to-cell transmission mechanism and related therapeutic development


α-Synucleinopathies is characterized with accumulation of misfolded α-synuclein (α-syn), including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). Emerging evidence indicates that pathogenesis of α-synucleinopathies may be due to cell-to-cell transmission of prion-like preformed fibrils (PFF) of α-syn. We identified several receptors (Lag3, Aplp1, neurexins) that specifically bind with α-syn fibrils but not α-syn monomer. Lymphocyte-activation gene-3 (Lag3) exhibits the highest binding affinity with α-syn fibrils, and α-syn fibrils binding to Lag3 initiated pathogenic α-syn endocytosis, propagation, transmission, and toxicity. Lack of Lag3 (Lag3-/-) substantially delay α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. To determine the neuronal Lag3 and the function in mediating α- synucleinopathies in vivo, we obtained the neuronal Lag3 conditional knockout mice (Lag3n-/-) and found that Lag3n-/- can significantly reduce the behavioral deficits induced by α-syn PFF. Furthermore, we have generated the human dopamine neurons derived from induced pluripotent stem cells (iPSCs) and successfully generated the α-syn PFF model in human neurons. Moreover, we determined the LAG3 expression in human neurons. The LAG3 expression can be up-regulated by progerin, an aging inducer, and the higher LAG3 expression has been confirmed in aged mice compared to young mice. LAG3 inhibitors (anti-LAG3, compound) can inhibit the endocytosis of α-syn PFF and subsequent α-syn pathology propagation and toxicity. The identification of Lag3 that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.

What will audience learn from your presentation?
• The molecular mechanism of pathogenic α-syn cell-to-cell transmission via LAG3
• LAG3 related therapeutic development against Parkinson’s disease and related α-synucleinopathies
• LAG3 antibody has been approved for cancer therapy, which encourage the application development in  neurodegenerative disorders


Dr. Mao received his PhD (Physical Chemistry) at the National Center for Nanoscience and Technology, Chinese Academy of Sciences in 2010. He then worked as postdoc in the labs of Profs. Drs. Ted and Valina Dawson at the Institute for Cell Engineering, Department of Neurology, Johns Hopkins School of Medicine (JHSOM) during 2010- 2016. After postdoctoral fellowship, he worked as Assistant Professor in 2017 and became Associate Professor in 2021 at JHSOM. He has published more than 50 research articles in many high-impact journals (Science, Nature, Nature Medicine, PNAS, Nature Comm, Nano Today) focusing on pathogenic protein cell-to-cell spreading.