Acta Neuropathologica

, Volume 133, Issue 3, pp 381–393

Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections

  • Ayse Ulusoy
  • Robert J. Phillips
  • Michael Helwig
  • Michael Klinkenberg
  • Terry L. Powley
  • Donato A. Di Monte
Original Paper

DOI: 10.1007/s00401-016-1661-y

Cite this article as:
Ulusoy, A., Phillips, R.J., Helwig, M. et al. Acta Neuropathol (2017) 133: 381. doi:10.1007/s00401-016-1661-y

Abstract

Detection of α-synuclein lesions in peripheral tissues is a feature of human synucleinopathies of likely pathogenetic relevance and bearing important clinical implications. Experiments were carried out to elucidate the relationship between α-synuclein accumulation in the brain and in peripheral organs, and to identify potential pathways involved in long-distance protein transfer. Results of this in vivo study revealed a route-specific transmission of α-synuclein from the rat brain to the stomach. Following targeted midbrain overexpression of human α-synuclein, the exogenous protein was capable of reaching the gastric wall where it was accumulated into preganglionic vagal terminals. This brain-to-stomach connection likely involved intra- and inter-neuronal transfer of non-fibrillar α-synuclein that first reached the medulla oblongata, then gained access into cholinergic neurons of the dorsal motor nucleus of the vagus nerve and finally traveled via efferent fibers of these neurons contained within the vagus nerve. Data also showed a particular propensity of vagal motor neurons and efferents to accrue α-synuclein and deliver it to peripheral tissues; indeed, following its midbrain overexpression, human α-synuclein was detected within gastric nerve endings of visceromotor but not viscerosensory vagal projections. Thus, the dorsal motor nucleus of the vagus nerve represents a key relay center for central-to-peripheral α-synuclein transmission, and efferent vagal fibers may act as unique conduits for protein transfer. The presence of α-synuclein in peripheral tissues could reflect, at least in some synucleinopathy patients, an ongoing pathological process that originates within the brain and, from there, reaches distant organs innervated by motor vagal projections.

Keywords

Adeno-associated virus Enteric nervous system Parkinson’s disease Rat Synucleinopathies Vagus nerve 

Supplementary material

401_2016_1661_MOESM1_ESM.pdf (29.7 mb)
Supplementary material 1 (PDF 30460 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ayse Ulusoy
    • 1
  • Robert J. Phillips
    • 2
  • Michael Helwig
    • 1
  • Michael Klinkenberg
    • 1
  • Terry L. Powley
    • 2
  • Donato A. Di Monte
    • 1
  1. 1.German Center for Neurodegenerative Diseases (DZNE)BonnGermany
  2. 2.Department of Psychological SciencesPurdue UniversityWest LafayetteUSA

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