Intercellular transfer of pathogenic α-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal

Neurobiol Aging. 2018 Jan;61:52-65. doi: 10.1016/j.neurobiolaging.2017.09.016. Epub 2017 Sep 22.

Abstract

Parkinson's disease (PD) is characterized by accumulations of toxic α-synuclein aggregates in vulnerable neuronal populations in the brainstem, midbrain, and cerebral cortex. Recent findings suggest that α-synuclein pathology can be propagated transneuronally, but the underlying molecular mechanisms are unknown. Advances in the genetics of rare early-onset familial PD indicate that increased production and/or reduced autophagic clearance of α-synuclein can cause PD. The cause of the most common late-onset PD is unclear, but may involve metabolic compromise and oxidative stress upstream of α-synuclein accumulation. As evidence, the lipid peroxidation product 4-hydroxynonenal (HNE) is elevated in the brain during normal aging and moreso in brain regions afflicted with α-synuclein pathology. Here, we report that HNE increases aggregation of endogenous α-synuclein in primary neurons and triggers the secretion of extracellular vesicles (EVs) containing cytotoxic oligomeric α-synuclein species. EVs released from HNE-treated neurons are internalized by healthy neurons which as a consequence degenerate. Levels of endogenously generated HNE are elevated in cultured cells overexpressing human α-synuclein, and EVs released from those cells are toxic to neurons. The EV-associated α-synuclein is located both inside the vesicles and on their surface, where it plays a role in EV internalization by neurons. On internalization, EVs harboring pathogenic α-synuclein are transported both anterogradely and retrogradely within axons. Focal injection of EVs containing α-synuclein into the striatum of wild-type mice results in spread of synuclein pathology to anatomically connected brain regions. Our findings suggest a scenario for late-onset PD in which lipid peroxidation promotes intracellular accumulation and then extrusion of EVs containing toxic α-synuclein species; the EVs are then internalized by adjacent neurons, so propagating the neurodegenerative process.

Keywords: 4-hydroxynonenal; Exosomes; Extracellular vesicles; Lipid peroxidation; Parkinson's disease; Striatum; α-synuclein.

MeSH terms

  • Aldehydes / metabolism*
  • Animals
  • Axons / metabolism
  • Biological Transport
  • Brain / metabolism
  • Cells, Cultured
  • Extracellular Vesicles / metabolism*
  • HEK293 Cells
  • Humans
  • Lipid Peroxidation*
  • Mice, Transgenic
  • Neurons / metabolism
  • Oxidative Stress
  • Parkinson Disease / etiology*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • alpha-Synuclein / metabolism*
  • alpha-Synuclein / physiology

Substances

  • Aldehydes
  • alpha-Synuclein
  • 4-hydroxy-2-nonenal