Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo

In Parkinson's disease and dementia with Lewy bodies, alpha-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic alpha-synuclein species remains unclear. A number of synthetic alpha-synuclein mutations were recently created (E57K and E35K) that produce species of alpha-synuclein that preferentially form oligomers and increase alpha-synuclein-mediated toxicity. We have shown that acute lentiviral expression of alpha-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone alpha-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 alpha-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 alpha-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 alpha-synuclein wild-type mouse model (Line 61), which accumulates various forms of alpha-synuclein. Three lines of alpha-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The alpha-synuclein E57K Lines 9 and 16 were higher expressings of alpha-synuclein, similar to alpha-synuclein wild-type Line 61, and Line 54 was a low expressing of alpha-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing alpha-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, alpha-synuclein whereas lower-expressing mice accumulated monomeric alpha-synuclein. Monomers, oligomers, and fibrils were present in alpha-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that alpha-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the alpha-synuclein wild-type Line 61, which accumulates alpha-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing alpha-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 alpha-synuclein wild-type mice. Moreover, although the oligomer-prone alpha-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the alpha-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric alpha-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.