中科院纳米生物效应与安全性重点实验室
纳米技术论坛(NS Forum No. 299)
第299期学术报告会通知 

题  目：Pathological Alpha-synuclein Spreading Mechanism
报告人：毛晓波教授, 美国约翰霍普金斯大学 
时  间：2018年6月29日（星期五）上午9点 
地  点：国家纳米科学中心，南楼三层会议室 
主持人：王  琛 研究员, 杨延莲 研究员 

报告摘要:
        Parkinson’s disease (PD) is the second most common neurodegenerative disorder causing serious movement disability and cognitive impairment in those afflicted. Pathologically, PD is characterized by the accumulation of α-synuclein (α-syn) in Lewy bodies and neurites. There is dopamine neuron degeneration in the substantia nigra pars compacta which causes many of the major symptoms of PD. Emerging evidence indicates that the pathogenesis of PD may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-syn. The mechanism by which α-syn PFF spreads from neuron to neuron is not known.
      Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. Tau-biotin PFF, β-amyloid-biotin oligomer, and β-amyloid-biotin PFF do not bind to LAG3, indicating that LAG3 is specific for α-syn PFF. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Neuron-to-neuron transmission of pathologic α-synuclein and the accompanying pathology and neurotoxicity is substantially attenuated by deletion of LAG3 or by antibodies to LAG3. Lack of LAG3 substantially delayed α-syn PFF–induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies. Furthermore, we have discovered another essential receptor APLP1 that mediates α-syn PFF internalization and spreading in vitro and in vivo. APLP1 and LAG3 binds with each other, and the APLP1-LAG3 complex can more efficiently bind with α-syn PFF and coordinately mediate the internalization of α-syn PFF.