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Cell Rep. 2014 Jun 26;7(6):2054-65. doi: 10.1016/j.celrep.2014.05.033. Epub 2014 Jun 12.

Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration.

Author information

1
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute of Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
2
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.

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.

PMID:
24931606
PMCID:
PMC4410967
DOI:
10.1016/j.celrep.2014.05.033
[Indexed for MEDLINE]
Free PMC Article

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