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

Rockenstein E, Nuber S, Overk CR, Ubhi K, Mante M, Patrick C, Adame A, Trejo-Morales M, Gerez J, Picotti P, Jensen PH, Campioni S, Riek R, Winkler J, Gage FH, Winner B, Masliah E (2014)

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Publication Type: Journal article

Publication year: 2014

Journal

Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 137

Pages Range: 1496-513

Journal Issue: Pt 5

DOI: 10.1093/brain/awu057

Abstract

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

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APA:

Rockenstein, E., Nuber, S., Overk, C.R., Ubhi, K., Mante, M., Patrick, C.,... Masliah, E. (2014). Accumulation of oligomer-prone ?-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain, 137(Pt 5), 1496-513. https://doi.org/10.1093/brain/awu057

MLA:

Rockenstein, Edward, et al. "Accumulation of oligomer-prone ?-synuclein exacerbates synaptic and neuronal degeneration in vivo." Brain 137.Pt 5 (2014): 1496-513.

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