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

ABSTRACT: In Parkinson's disease (PD) there is widespread accumulation in the brain of abnormal ?-synuclein aggregates forming intraneuronal Lewy bodies (LB). It is now well established that LB-type ?-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 ?-synuclein aggregates we have previously shown that LB purified from postmortem PD brains promote ?-synuclein pathology and dopaminergic neurodegeneration when intracerebrally inoculated into wild-type mice. However, the pathogenic capacity of PD-derived peripheral ?-synuclein aggregates remains unknown. Here we addressed this question using purified LB-type ?-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 ?-synuclein pathology. The differential pathogenic capacities of central- and peripheral-derived ?-synuclein aggregates appear independent of the absolute amount and basic biochemical properties of ?-synuclein within these aggregates and may rely instead on differences in ?-synuclein conformation and/or yet unrecognized brain region-specific intrinsic factors. Our results argue against a putative pathogenic capacity of peripheral ?-synuclein aggregates to promote ?-synuclein pathology in the brain, propagate between neuronal networks or induce neurodegeneration.

SUBMITTER: Recasens A 

PROVIDER: S-EPMC5806361 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature