期刊
BRAIN
卷 136, 期 -, 页码 412-432出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/aws358
关键词
Parkinson's disease; dopamine; animal models; alpha-synuclein; synapse function
资金
- European Community (Ratstream) [EU FP6-037846]
- MEFOPA [241791]
- fortune [F.15.13141]
- NIH [AG 18440, AG 022074]
- Interdisciplinary Centre for Clinical Research (IZKF) at the FAU Erlangen-Nuernberg (Germany)
- Bavarian State Ministry of Sciences, Research
- Arts, ForNeuroCell (Germany)
- German Ministry for Education and Science (BMBF) [01GN0979]
- Albert Raps Foundation (Kulmbach, Germany)
- Parkinson's UK, a charity registered in England and Wales [258197, SC037554]
- Parkinson's UK [G-0909] Funding Source: researchfish
Conversion of soluble alpha-synuclein into insoluble and fibrillar inclusions is a hallmark of Parkinson's disease and other synucleinopathies. Accumulating evidence points towards a relationship between its generation at nerve terminals and structural synaptic pathology. Little is known about the pathogenic impact of alpha-synuclein conversion and deposition at nigrostriatal dopaminergic synapses in transgenic mice, mainly owing to expression limitations of the alpha-synuclein construct. Here, we explore whether both the rat as a model and expression of the bacterial artificial chromosome construct consisting of human full-length wild-type alpha-synuclein could exert dopaminergic neuropathological effects. We found that the human promoter induced a pan-neuronal expression, matching the rodent alpha-synuclein expression pattern, however, with prominent C-terminally truncated fragments. Ageing promoted conversion of both full-length and C-terminally truncated alpha-synuclein species into insolube and proteinase K-resistant fibres, with strongest accumulation in the striatum, resembling biochemical changes seen in human Parkinson's disease. Transgenic rats develop early changes in novelty-seeking, avoidance and smell before the progressive motor deficit. Importantly, the observed pathological changes were associated with severe loss of the dopaminergic integrity, thus resembling more closely the human pathology.
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