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Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

Mao, Xiaobo, Ou, Michael Tianhao, Karuppagounder, Senthilkumar S., Kam, Tae-In, Yin, Xiling, Xiong, Yulan, Ge, Preston, Umanah, George Essien, Brahmachari, Saurav, Shin, Joo-Ho, Kang, Ho Chul, Zhang, Jianmin, Xu, Jinchong, Chen, Rong, Park, Hyejin, Andrabi, Shaida A., Kang, Sung Ung, Gonçalves, Rafaella Araújo, Liang, Yu, Zhang, Shu, Qi, Chen, Lam, Sharon, Keiler, James A., Tyson, Joel, Kim, Donghoon, Panicker, Nikhil, Yun, Seung Pil, Workman, Creg J., Vignali, Dario A. A., Dawson, Valina L., Ko, Han Seok, Dawson, Ted M.·2016·Science
DOI 10.1126/science.aah3374PMC PMC5510615
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Abstract

INTRODUCTION: Parkinson’s disease (PD) is the second most common neurodegenerative disorder and leads to slowness of movement, tremor, rigidity, and, in the later stages of PD, cognitive impairment. Pathologically, PD is characterized by the accumulation of α-synuclein in Lewy bodies and neurites. There is degeneration of neurons throughout the nervous system, with the degeneration of dopamine neurons in the substantia nigra pars compacta leading to the major symptoms of PD. RATIONALE: In the brains of PD patients, pathologic α-synuclein seems to spread from cell to cell via self-amplification, propagation, and transmission in a stereotypical and topographical pattern among neighboring cells and/or anatomically connected brain regions. The spread or transmission of pathologic α-synuclein is emerging as a potentially important driver of PD pathogenesis. The underlying mechanisms and molecular entities responsible for the transmission of pathologic α-synuclein from cell to cell are not known, but the entry of pathologic α-synuclein into neurons is thought to occur, in part, through an active clathrin-dependent endocytic process. RESULTS: Using recombinant α-synuclein preformed fibrils (PFF) as a model system with which to study the transmission of misfolded α-synuclein from neuron to neuron, we screened a library encoding transmembrane proteins for α-synuclein-biotin PFF–binding candidates via detection with streptavidin-AP (alkaline phosphatase) staining. Three positive clones were identified that bind α-synuclein PFF and include lymphocyte-activation gene 3 (LAG3), neurexin 1β, and amyloid β precursor-like protein 1 (APLP1). Of these three transmembrane proteins, LAG3 demonstrated the highest ratio of selectivity for α-synuclein PFF over the α-synuclein monomer. α-Synuclein PFF bind to LAG3 in a saturable manner (dissociation constant = 77 nM), whereas the α-synuclein monomer does not bind to LAG3. Co-immunoprecipitation also suggests that pathological α-synuclein PFF specifically bind to LAG3. Tau PFF, β-amyloid oligomer, and β-amyloid PFF do not bind to LAG3, indicating that LAG3 is specific for α-synuclein PFF. The internalization of α-synuclein PFF involves LAG3 because deletion of LAG3 reduces the endocytosis of α-synuclein PFF. LAG3 colocalizes with the endosomal guanosine triphosphatases Rab5 and Rab7 and coendocytoses with pathologic α-synuclein. 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. The lack of LAG3 also substantially delayed α-synuclein PFF–induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. CONCLUSION: We discovered that pathologic α-synuclein transmission and toxicity is initiated by binding to LAG3 and that neuron-to-neuron transmission of pathological α-synuclein involves the endocytosis of exogenous α-synuclein PFF by the engagement of LAG3 on neurons. Depletion of LAG3 or antibodies to LAG3 substantially reduces the pathology set in motion by the transmission of pathologic α-synuclein. The identification of LAG3 as an α-synuclein PFF–binding protein provides a new target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies. LAG3 deletion or antibodies to LAG3 delay α-synuclein PFF transmission.: Compared with wild-type neurons, binding and endocytosis of α-synuclein PFF is dramatically reduced with antibodies to LAG3 or when LAG3 is deleted, resulting in delayed pathologic α-synuclein transmission and toxicity. Illustration credit: I-Hsun Wu

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  • LAG3 specifically binds to α-Syn PFFs but not monomers.

    “Notably, LAG3 specifically binds to α-Syn PFFs but not monomers.”

    From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [41]

  • LAG3 is a receptor for α-Syn PFFs that mediates endocytosis and transmission of α-Syn PFFs between neurons.

    “A recent study showed that the lymphocyte-activation gene 3 (LAG3) is a receptor for α-Syn PFFs which mediates the endocytosis and transmission of α-Syn PFFs between neurons [41].”

    From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [41]

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Metadata

Authors
Mao, X., Ou, M. T., Karuppagounder, S. S., Kam, T.-I., Yin, X., Xiong, Y., Ge, P., Umanah, G. E., Brahmachari, S., Shin, J.-H., Kang, H. C., Zhang, J., Xu, J., Chen, R., Park, H., Andrabi, S. A., Kang, S. U., Gonçalves, R. A., Liang, Y., Zhang, S., Qi, C., Lam, S., Keiler, J. A., Tyson, J., Kim, D., Panicker, N., Yun, S. P., Workman, C. J., Vignali, D. A. A., Dawson, V. L., Ko, H. S., & Dawson, T. M.
Affiliations
  • Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2016-09-30
Volume
353
Issue
6307
ISSN
  • 0036-8075
  • 1095-9203
DOI
10.1126/science.aah3374
PMC
PMC5510615
Cited by
690
References
12
Language
en
Funders
  • JPB Foundation
  • Parkinson's Disease Foundation (PDF-SFW-1572)
  • NIH/National Institute on Aging (K01-AG046366)
  • The William N. & Bernice E. Bumpus Foundation Innovation Awards
  • National Institute of Neurological Disorders and Stroke (NS082205)
  • NIH (NS38377, P01-AI108545)

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