Lack of pathogenic potential of peripheral α-synuclein aggregates from Parkinson's disease patients

Acta Neuropathol Commun. 2018 Feb 8;6(1):8. doi: 10.1186/s40478-018-0509-1.

Abstract

In Parkinson's disease (PD) there is widespread accumulation in the brain of abnormal α-synuclein aggregates forming intraneuronal Lewy bodies (LB). It is now well established that LB-type α-synuclein aggregates also occur in the peripheral autonomic nervous system in PD, from where it has been speculated they may progressively spread to the central nervous system through synaptically-connected brain networks and reach the substantia nigra to trigger herein dopaminergic dysfunction/degeneration and subsequent parkinsonism. Supporting a pathogenic role for α-synuclein aggregates we have previously shown that LB purified from postmortem PD brains promote α-synuclein pathology and dopaminergic neurodegeneration when intracerebrally inoculated into wild-type mice. However, the pathogenic capacity of PD-derived peripheral α-synuclein aggregates remains unknown. Here we addressed this question using purified LB-type α-synuclein aggregates from postmortem PD stellate ganglia (SG), a paravertebral sympathetic ganglion that exhibits consistent and conspicuous Lewy pathology in all PD patients. In contrast to our previous findings using nigral LB extracts, intracerebral inoculation of SG-derived LB into mice did not trigger long-term nigrostriatal neurodegeneration nor α-synuclein pathology. The differential pathogenic capacities of central- and peripheral-derived α-synuclein aggregates appear independent of the absolute amount and basic biochemical properties of α-synuclein within these aggregates and may rely instead on differences in α-synuclein conformation and/or yet unrecognized brain region-specific intrinsic factors. Our results argue against a putative pathogenic capacity of peripheral α-synuclein aggregates to promote α-synuclein pathology in the brain, propagate between neuronal networks or induce neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Female
  • Humans
  • Lewy Bodies / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Parkinson Disease / metabolism*
  • Protein Aggregation, Pathological / metabolism*
  • Stellate Ganglion / metabolism*
  • alpha-Synuclein / administration & dosage
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / isolation & purification
  • alpha-Synuclein / metabolism*

Substances

  • SNCA protein, human
  • alpha-Synuclein