@a-Synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfolded @a-Synuclein and Neurodegeneration

摘要

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