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Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration.
Cell Rep. 2014 Jun 26; 7(6):2054-65.CR

Abstract

Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson's disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.

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Authors+Show Affiliations

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. Electronic address: vmylee@upenn.edu.

MeSH

AnimalsAntibodies, MonoclonalFemaleImmunotherapyLewy Body DiseaseMaleMiceNeuronsParkinson Diseasealpha-Synuclein

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24931606

Citation

Tran, Hien T., et al. "Α-synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfolded Α-synuclein and Neurodegeneration." Cell Reports, vol. 7, no. 6, 2014, pp. 2054-65.

Tran HT, Chung CH, Iba M, et al. Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 2014;7(6):2054-65.

Tran, H. T., Chung, C. H., Iba, M., Zhang, B., Trojanowski, J. Q., Luk, K. C., & Lee, V. M. (2014). Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Reports, 7(6), 2054-65. https://doi.org/10.1016/j.celrep.2014.05.033

Tran HT, et al. Α-synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfolded Α-synuclein and Neurodegeneration. Cell Rep. 2014 Jun 26;7(6):2054-65. PubMed PMID: 24931606.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. AU - Tran,Hien T, AU - Chung,Charlotte Hiu-Yan, AU - Iba,Michiyo, AU - Zhang,Bin, AU - Trojanowski,John Q, AU - Luk,Kelvin C, AU - Lee,Virginia M Y, Y1 - 2014/06/12/ PY - 2013/11/04/received PY - 2014/03/16/revised PY - 2014/05/15/accepted PY - 2014/6/17/entrez PY - 2014/6/17/pubmed PY - 2015/4/17/medline SP - 2054 EP - 65 JF - Cell reports JO - Cell Rep VL - 7 IS - 6 N2 - Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson's disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons. SN - 2211-1247 UR - https://www.unboundmedicine.com/medline/citation/24931606/��_synuclein_immunotherapy_blocks_uptake_and_templated_propagation_of_misfolded_��_synuclein_and_neurodegeneration_ DB - PRIME DP - Unbound Medicine ER -