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

ABSTRACT: Accumulation of misfolded alpha-synuclein (?-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 ?-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological ?-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that ?-syn monoclonal antibodies (mAbs) reduce ?-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 ?-syn into nontransgenic mice injected intrastriatally with ?-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that ?-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological ?-syn and/or its propagation in neurons.

SUBMITTER: Tran HT

PROVIDER: S-EPMC4410967 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Tran Hien T HT Chung Charlotte Hiu-Yan CH Iba Michiyo M Zhang Bin B Trojanowski John Q JQ Luk Kelvin C KC Lee Virginia M Y VM

Cell reports 20140612 6

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 ...[more]

PMID: 24931606

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Project description:BackgroundSynucleinopathies of the aging population are an heterogeneous group of neurological disorders that includes Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and are characterized by the progressive accumulation of α-synuclein in neuronal and glial cells. Toll-like receptor 2 (TLR2), a pattern recognition immune receptor, has been implicated in the pathogenesis of synucleinopathies because TLR2 is elevated in the brains of patients with PD and TLR2 is a mediator of the neurotoxic and pro-inflammatory effects of extracellular α-synuclein aggregates. Therefore, blocking TLR2 might alleviate α-synuclein pathological and functional effects. For this purpose, herein, we targeted TLR2 using a functional inhibitory antibody (anti-TLR2).MethodsTwo different human α-synuclein overexpressing transgenic mice were used in this study. α-synuclein low expresser mouse (α-syn-tg, under the PDGFβ promoter, D line) was stereotaxically injected with TLR2 overexpressing lentivirus to demonstrate that increment of TLR2 expression triggers neurotoxicity and neuroinflammation. α-synuclein high expresser mouse (α-Syn-tg; under mThy1 promoter, Line 61) was administrated with anti-TLR2 to examine that functional inhibition of TLR2 ameliorates neuropathology and behavioral defect in the synucleinopathy animal model. In vitro α-synuclein transmission live cell monitoring system was used to evaluate the role of TLR2 in α-synuclein cell-to-cell transmission.ResultsWe demonstrated that administration of anti-TLR2 alleviated α-synuclein accumulation in neuronal and astroglial cells, neuroinflammation, neurodegeneration, and behavioral deficits in an α-synuclein tg mouse model of PD/DLB. Moreover, in vitro studies with neuronal and astroglial cells showed that the neuroprotective effects of anti-TLR2 antibody were mediated by blocking the neuron-to-neuron and neuron-to-astrocyte α-synuclein transmission which otherwise promotes NFκB dependent pro-inflammatory responses.ConclusionThis study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population.

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

Publications

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

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