期刊
ANNALS OF NEUROLOGY
卷 66, 期 4, 页码 472-484出版社
WILEY-BLACKWELL
DOI: 10.1002/ana.21716
关键词
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资金
- National Health and Medical Research Council (NHMRC) of Australia
- NHMRC CJ Martin Fellowship
- Brain Foundations
- Bethlehem Griffiths Research Foundation
Objective: This study questions whether increased dopamine (DA) turnover in nigral neurons leads to formation of Lewy bodies (LBs), the characteristic alpha-synuclein-containing cytoplasmic inclusion of Parkinson disease (PD). Methods: Mice with targeted deletion of the dopamine D-2 receptor gene (D2R[-/-]) have higher striatal and nigral dopamine turnover and elevated oxidative stress. These mice were examined for evidence of histological, biochemical, and gene expression changes consistent with a synucleinopathy. Results: LB-like cytoplasmic inclusions containing alpha-synuclein and ubiquitin were present in substantia nigra pars compacta (SNpc) neurons of older D2R(-/-) mice, and were also occasionally seen in aged wild-type mice. These inclusions displaced the nucleus of affected cells and were eosinophilic. Diffuse cytosolic alpha-synuclein immunoreactivity in SNpc neurons increased with age in both wild-type and D2R(-/-) mice, most likely because of redistribution of alpha-synuclein from striatal terminals to SNpc cell bodies. Gene and protein expression studies indicated endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways in D2R(-/-) SNpc. These changes were accompanied by a loss of DA terminals in the dorsal striatum, although there was no evidence of progressive cell death in the SNpc. Interpretation: Increased sprouting and DA turnover, as observed in PD and D2R(-/-) mice, augments LB-like inclusions and axonal degeneration of dopaminergic neurons. These changes are associated with ER stress and autophagy.
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