[HTML][HTML] α-Synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration

HT Tran, CHY Chung, M Iba, B Zhang, JQ Trojanowski… - Cell reports, 2014 - cell.com
HT Tran, CHY Chung, M Iba, B Zhang, JQ Trojanowski, KC Luk, VMY Lee
Cell reports, 2014cell.com
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 …
Summary
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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