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Poul Henning Jensen

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

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  • Edward Rockenstein, University of California at San Diego
  • ,
  • Silke Nuber
  • ,
  • Cassia R Overk
  • ,
  • Kiren Ubhi
  • ,
  • Michael Mante
  • ,
  • Christina Patrick
  • ,
  • Anthony Adame
  • ,
  • Margarita Trejo-Morales
  • ,
  • Juan Gerez
  • ,
  • Paola Picotti
  • ,
  • Poul H Jensen
  • Silvia Campioni
  • ,
  • Roland Riek
  • ,
  • Jürgen Winkler
  • ,
  • Fred H Gage
  • ,
  • Beate Winner
  • ,
  • Eliezer Masliah

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.

Original languageEnglish
IssuePt 5
Pages (from-to)1496-513
Number of pages18
Publication statusPublished - May 2014

    Research areas

  • Alzheimer Disease, Animals, Antigens, Thy-1, Brain, Disease Models, Animal, Gene Expression Regulation, Glutamic Acid, Humans, Lewy Body Disease, Lysine, Memory Disorders, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Degeneration, Nerve Tissue Proteins, Neurons, Synapses, alpha-Synuclein

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