期刊
JOURNAL OF NEUROSCIENCE RESEARCH
卷 99, 期 10, 页码 2525-2539出版社
WILEY
DOI: 10.1002/jnr.24927
关键词
A30P; alpha-synuclein; oligomers; Parkinson's disease; proximity ligation assay; pS129
资金
- Swedish Research Council [MI:2018-03075]
- Torsten Soderberg Foundation
- Swedish Parkinson Foundation
- Swedish Brain Foundation
- Swedish Alzheimer Foundation
- Swedish Dementia Association
- Magnus Bergwall Foundation
- Ahlen Foundation
- King Gustaf V's, and Queen Victoria's Freemason Foundation
- Sigurd and Elsa Goljes memory foundation
- Stohnes foundation
- Swedish Research Council [2018-03075] Funding Source: Swedish Research Council
The study revealed an abundance of previously undetected α-syn oligomers in the midbrain of young A30P transgenic mice, while phosphorylated and proteinase k-resistant α-syn species were observed to a larger extent in aged mice. Although no loss of dopaminergic neurons was detected in A30P transgenic mice, dysregulation in the monoaminergic system was recorded in older mice.
Aggregation of alpha-synuclein (alpha-syn) into Lewy bodies and Lewy neurites is a pathological hallmark in the Parkinson ' s disease (PD) brain. The formation of alpha-syn oligomers is believed to be an early pathogenic event and the A30P mutation in the gene encoding alpha-syn, causing familial PD, has been shown to cause an accelerated oligomerization. Due to the problem of preserving antigen conformation on tissue surfaces, alpha-syn oligomers are difficult to detect ex vivo using conventional immunohistochemistry with oligomer-selective antibodies. Herein, we have instead employed the previously reported alpha-syn oligomer proximity ligation assay (ASO-PLA), along with a wide variety of biochemical assays, to discern the pathological progression of alpha-syn oligomers and their impact on the dopaminergic system in male and female (Thy-1)-h[A30P]alpha-syn transgenic (A30P-tg) mice. Our results reveal a previously undetected abundance of alpha-syn oligomers in midbrain of young mice, whereas phosphorylated (pS129) and proteinase k-resistant alpha-syn species were observed to a larger extent in aged mice. Although we did not detect loss of dopaminergic neurons in A30P-tg mice, a dysregulation in the monoaminergic system was recorded in older mice. Taken together, ASO-PLA should be a useful method for the detection of early changes in alpha-syn aggregation on brain tissue, from experimental mouse models in addition to post mortem PD cases.
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