α-Synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfolded α-Synuclein and Neurodegeneration
Hien T. Tran,
Charlotte Hiu-Yan Chung,
Michiyo Iba,
Bin Zhang,
John Q. Trojanowski,
Kelvin C. Luk,
Virginia M.Y. Lee
Affiliations
Hien T. Tran
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Charlotte Hiu-Yan Chung
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Michiyo Iba
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Bin Zhang
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
John Q. Trojanowski
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Kelvin C. Luk
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Virginia M.Y. Lee
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
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.
