Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.

Academic Article

Abstract

  • Inclusions composed of α-synuclein (α-syn), i.e., Lewy bodies (LBs) and Lewy neurites (LNs), define synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Here, we demonstrate that preformed fibrils generated from full-length and truncated recombinant α-syn enter primary neurons, probably by adsorptive-mediated endocytosis, and promote recruitment of soluble endogenous α-syn into insoluble PD-like LBs and LNs. Remarkably, endogenous α-syn was sufficient for formation of these aggregates, and overexpression of wild-type or mutant α-syn was not required. LN-like pathology first developed in axons and propagated to form LB-like inclusions in perikarya. Accumulation of pathologic α-syn led to selective decreases in synaptic proteins, progressive impairments in neuronal excitability and connectivity, and, eventually, neuron death. Thus, our data contribute important insights into the etiology and pathogenesis of PD-like α-syn inclusions and their impact on neuronal functions, and they provide a model for discovering therapeutics targeting pathologic α-syn-mediated neurodegeneration.
  • Published In

  • Neuron  Journal
  • Keywords

  • Animals, Axonal Transport, Cell Death, Endocytosis, Hippocampus, Humans, Lewy Bodies, Mice, Mice, Inbred C57BL, Nerve Degeneration, Nerve Tissue Proteins, Neurites, Neurons, Primary Cell Culture, Synapses, Voltage-Sensitive Dye Imaging, alpha-Synuclein
  • Digital Object Identifier (doi)

    Author List

  • Volpicelli-Daley LA; Luk KC; Patel TP; Tanik SA; Riddle DM; Stieber A; Meaney DF; Trojanowski JQ; Lee VM-Y
  • Start Page

  • 57
  • End Page

  • 71
  • Volume

  • 72
  • Issue

  • 1