title: Direct detection of alpha synuclein oligomers in vivo.
abstract: BACKGROUND
  Rat models of Parkinson's disease are widely used to elucidate the mechanisms underlying disease etiology or to investigate therapeutic approaches. Models were developed using toxins such as MPTP or 6-OHDA to specifically target dopaminergic neurons resulting in acute neuronal loss in the substantia nigra or by using viral vectors to induce the specific and gradual expression of alpha synuclein in the substantia nigra. The detection of alpha- synuclein oligomers, the presumed toxic species, in these models and others has been possible using only indirect biochemical approaches to date. Here we coinjected AAVs encoding alpha-synuclein fused to the N- or C-terminal half of VenusYFP in rat substantia nigra pars compacta and describe for the first time a novel viral vector rodent model with the unique ability to directly detect and track alpha synuclein oligomers ex vivo and in vivo.
  
  
  RESULTS
  Viral coinjection resulted in widespread VenusYFP signal within the nigrostriatal pathway, including cell bodies in the substantia nigra and synaptic accumulation in striatal terminals, suggestive of in vivo alpha-synuclein oligomers formation. Transduced rats showed alpha-synuclein induced dopaminergic neuron loss in the substantia nigra, the appearance of dystrophic neurites, and gliosis in the striatum. Moreover, we have applied in vivo imaging techniques in the living mouse to directly image alpha-synuclein oligomers in the cortex.
  
  
  CONCLUSIONS
  We have developed a unique animal model that provides a tool for the Parkinson's disease research community with which to directly detect alpha- synuclein oligomers in vivo and screen therapeutic approaches targeting alpha-synuclein oligomers.
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Department Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. mclean.pamela@mayo.edu.
authors.forename: Hemi
authors.initials: H
authors.lastname: Dimant
authors.forename: Suneil K
authors.initials: SK
authors.lastname: Kalia
authors.forename: Lorraine V
authors.initials: LV
authors.lastname: Kalia
authors.forename: Liya N
authors.initials: LN
authors.lastname: Zhu
authors.forename: Laura
authors.initials: L
authors.lastname: Kibuuka
authors.forename: Darius
authors.initials: D
authors.lastname: Ebrahimi-Fakhari
authors.forename: Nikolaus R
authors.initials: NR
authors.lastname: McFarland
authors.forename: Zhanyun
authors.initials: Z
authors.lastname: Fan
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry* / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology / Q000502:physiology; D005822:Genetic Vectors; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D015213:Neuroimmunomodulation / Q000502:physiology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000737:chemistry* / Q000473:pathology; D051844:alpha-Synuclein / Q000032:analysis* / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein; C054562:yellow fluorescent protein, Bacteria