Alpha-Synuclein transgenic mice, h-α-SynL62, display α-Syn aggregation and a dopaminergic phenotype reminiscent of Parkinson's disease

Behav Brain Res. 2018 Feb 26;339:153-168. doi: 10.1016/j.bbr.2017.11.025. Epub 2017 Nov 24.


Alpha-Synuclein (α-Syn) accumulation is considered a major risk factor for the development of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. We have generated mice overexpressing full-length human α-Syn fused to a membrane-targeting signal sequence under the control of the mouse Thy1-promotor. Three separate lines (L56, L58 and L62) with similar gene expression levels, but considerably heightened protein accumulation in L58 and L62, were established. In L62, there was widespread labelling of α-Syn immunoreactivity in brain including spinal cord, basal forebrain, cortex and striatum. Interestingly, there was no detectable α-Syn expression in dopaminergic neurones of the substantia nigra, but strong human α-Syn reactivity in glutamatergic synapses. The human α-Syn accumulated during aging and formed PK-resistant, thioflavin-binding aggregates. Mice displayed early onset bradykinesia and age progressive motor deficits. Functional alterations within the striatum were confirmed: L62 showed normal basal dopamine levels, but impaired dopamine release (upon amphetamine challenge) in the dorsal striatum measured by in vivo brain dialysis at 9 months of age. This impairment was coincident with a reduced response to amphetamine in the activity test. L62 further displayed greater sensitivity to low doses of the dopamine receptor 1 (D1) agonist SKF81297 but reacted normally to the D2 agonist quinpirole in the open field. Since accumulation of α-Syn aggregates in neurones and synapses and alterations in the dopaminergic tone are characteristics of PD, phenotypes reported for L62 present a good opportunity to further our understanding of motor dysfunction in PD and Lewy body dementia.

Keywords: Glutamate; Motor dysfunction; Parkinson’s disease; Protein aggregation; α-Synuclein.

MeSH terms

  • Animals
  • Corpus Striatum / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Dopaminergic Neurons / metabolism*
  • Mice, Transgenic
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Phenotype
  • Substantia Nigra / metabolism
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism


  • Snca protein, mouse
  • alpha-Synuclein
  • Dopamine