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Pathological ?-synuclein transmission initiated by binding lymphocyte-activation gene 3.

ABSTRACT: Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of ?-synuclein (?-syn). The mechanism by which ?-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds ?-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the ?-syn monomer exhibited minimal binding. ?-Syn-biotin PFF binding to LAG3 initiated ?-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed ?-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 ?-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related ?-synucleinopathies.

SUBMITTER: Mao X

PROVIDER: S-EPMC5510615 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Mao Xiaobo X Ou Michael Tianhao MT Karuppagounder Senthilkumar S SS Kam Tae-In TI Yin Xiling X Xiong Yulan Y Ge Preston P Umanah George Essien GE Brahmachari Saurav S Shin Joo-Ho JH Kang Ho Chul HC Zhang Jianmin J Xu Jinchong J Chen Rong R Park Hyejin H Andrabi Shaida A SA Kang Sung Ung SU Gonçalves Rafaella Araújo RA Liang Yu Y Zhang Shu S Qi Chen C Lam Sharon S Keiler James A JA Tyson Joel J Kim Donghoon D Panicker Nikhil N Yun Seung Pil SP Workman Creg J CJ Vignali Dario A A DA Dawson Valina L VL Ko Han Seok HS Dawson Ted M TM

Science (New York, N.Y.) 20160901 6307

Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (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. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocyto ...[more]

PMID: 27708076

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Project description:BackgroundThe accumulation of misfolded proteins appears as a fundamental pathogenic process in human neurodegenerative diseases. In the case of synucleinopathies such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB), the intraneuronal deposition of aggregated alpha-synuclein (αS) is a major characteristic of the disease, but the molecular basis distinguishing the disease-associated protein (αSD) from its normal counterpart remains poorly understood. However, recent research suggests that a prion-like mechanism could be involved in the inter-cellular and inter-molecular propagation of aggregation of the protein within the nervous system.ResultsOur data confirm our previous observations of disease acceleration in a transgenic mouse line (M83) overexpressing a mutated (A53T) form of human αS, following inoculation of either brain extracts from sick M83 mice or fibrillar recombinant αS. A similar phenomenon is observed following a "second passage" in the M83 mouse model, including after stereotactic inoculations into the hippocampus or cerebellum. For further molecular analyses of αSD, we designed an ELISA test that identifies αSD specifically in sick mice and in the brain regions targeted by the pathological process in this mouse model. αSD distribution, mainly in the caudal brain regions and spinal cord, overall appears remarkably uniform, whatever the conditions of experimental challenge. In addition to specific detection of αSD immunoreactivity using an antibody against Ser129 phosphorylated αS, similar results were observed in ELISA with several other antibodies against the C-terminal part of αS, including an antibody against non phosphorylated αS. This also indicated consistent immunoreactivity of the murine αS protein specifically in the affected brain regions of sick mice.ConclusionsPrion-like behaviour in propagation of the disease-associated αS was confirmed with the M83 transgenic mouse model, that could be followed by an ELISA test. The ELISA data question their possible relationship with the conformational differences between the disease-associated αS and its normal counterpart.

Dataset Information

Pathological ?-synuclein transmission initiated by binding lymphocyte-activation gene 3.

Publications

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

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