title: Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein.
abstract: BACKGROUND
  α-Synuclein (αS) is the major component of several types of brain inclusions including Lewy bodies, a hallmark of Parkinson's disease. Aberrant aggregation of αS also is associated with cellular demise in multiple neurologic disorders collectively referred to as synucleinopathies. Recent studies demonstrate the induction of αS pathology by a single intracerebral injection of exogenous amyloidogenic αS in adult non-transgenic and transgenic mice expressing human αS. To further investigate the mechanism of pathology induction and evaluate an experimental paradigm with potential for higher throughput, we performed similar studies in neonatal mice injected with αS.
  
  
  RESULTS
  In non-transgenic mice, we observed limited induction of neuronal αS inclusions predominantly 8 months after brain injection of aggregated, amyloidogenic human αS. More robust inclusion pathology was induced in transgenic mice expressing wild-type human αS (line M20), and inclusion pathology was observed at earlier time points. Injection of a non-amyloidogenic (Δ71-82) deletion protein of αS was also able to induce similar pathology in a subset of M20 transgenic mice. M20 transgenic mice injected with amyloidogenic or non-amyloidogenic αS demonstrated a delayed and robust induction of brain neuroinflammation that occurs in mice with or without αS pathological inclusions implicating this mechanism in aggregate formation.
  
  
  CONCLUSIONS
  The finding that a non-amyloidogenic Δ71-82 αS can induce pathology calls into question the simple interpretation that exogenous αS catalyzes aggregation and spread of intracellular αS pathology solely through a nucleation dependent conformational templating mechanism. These results indicate that several mechanisms may act synergistically or independently to promote the spread of αS pathology.
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, BMS Building J-483, University of Florida College of Medicine, 1275 Center Drive, PO Box 100159, Gainesville, FL 32610, USA. tgolde@ufl.edu.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Sacino
authors.forename: Mieu
authors.initials: M
authors.lastname: Brooks
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: McGarvey
authors.forename: Alex B
authors.initials: AB
authors.lastname: McKinney
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thomas
authors.forename: Yona
authors.initials: Y
authors.lastname: Levites
authors.forename: Yong
authors.initials: Y
authors.lastname: Ran
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001921:Brain / Q000254:growth & development / Q000276:immunology* / Q000473:pathology; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology; D015213:Neuroimmunomodulation / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein