title: Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo.
abstract: In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may mediate early synaptic pathology in Parkinson's disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction.
authors.affiliation: 1 Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
authors.forename: Cassia R
authors.initials: CR
authors.lastname: Overk
authors.forename: Kiren
authors.initials: K
authors.lastname: Ubhi
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Margarita
authors.initials: M
authors.lastname: Trejo-Morales
authors.forename: Juan
authors.initials: J
authors.lastname: Gerez
authors.forename: Paola
authors.initials: P
authors.lastname: Picotti
authors.forename: Poul H
authors.initials: PH
authors.lastname: Jensen
authors.forename: Silvia
authors.initials: S
authors.lastname: Campioni
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000235:genetics; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D018800:Thy-1 Antigens; D051844:alpha-Synuclein; D018698:Glutamic Acid; D008239:Lysine
keywords: Parkinson’s disease; oligomer; synaptic vesicles; transgenic; α-synuclein