Caudo-rostral brain spreading of α-synuclein through vagal connections

EMBO Mol Med. 2013 Jul;5(7):1119-27. doi: 10.1002/emmm.201302475. Epub 2013 May 23.


α-Synuclein accumulation and pathology in Parkinson's disease typically display a caudo-rostral pattern of progression, involving neuronal nuclei in the medulla oblongata at the earliest stages. In this study, selective expression and accumulation of human α-synuclein within medullary neurons was achieved via retrograde transport of adeno-associated viral vectors unilaterally injected into the vagus nerve in the rat neck. The exogenous protein progressively spread toward more rostral brain regions where it could be detected within axonal projections. Propagation to the pons, midbrain and forebrain followed a stereotypical pattern of topographical distribution. It affected areas such as the coeruleus-subcoeruleus complex, dorsal raphae, hypothalamus and amygdala ipsilateral and, to a lesser extent, contralateral to the injection side. Spreading was accompanied by evidence of neuritic pathology in the form of axonal varicosities intensely immunoreactive for human α-synuclein and containing Thioflavin-S-positive fibrils. Thus, overexpression of human α-synuclein in the lower brainstem is sufficient to induce its long-distance caudo-rostral propagation, recapitulating features of Parkinson's disease and mechanisms of disease progression.

Keywords: Adeno-associated virus; Parkinson's disease; protein transport; rat; vagus nerve.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Brain / metabolism
  • Brain / pathology*
  • Brain Stem / metabolism
  • Brain Stem / pathology*
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Humans
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology*
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation
  • Vagus Nerve / metabolism
  • Vagus Nerve / pathology*
  • alpha-Synuclein / analysis
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • alpha-Synuclein