Journal of Neuroscience Research | 2021
Visualization of early oligomeric α‐synuclein pathology and its impact on the dopaminergic system in the (Thy‐1)‐h[A30P]α‐syn transgenic mouse model
Abstract
Aggregation of alpha‐synuclein (α‐syn) into Lewy bodies and Lewy neurites is a pathological hallmark in the Parkinson´s disease (PD) brain. The formation of α‐syn oligomers is believed to be an early pathogenic event and the A30P mutation in the gene encoding α‐syn, causing familial PD, has been shown to cause an accelerated oligomerization. Due to the problem of preserving antigen conformation on tissue surfaces, α‐syn oligomers are difficult to detect ex vivo using conventional immunohistochemistry with oligomer‐selective antibodies. Herein, we have instead employed the previously reported α‐syn oligomer proximity ligation assay (ASO‐PLA), along with a wide variety of biochemical assays, to discern the pathological progression of α‐syn oligomers and their impact on the dopaminergic system in male and female (Thy‐1)‐h[A30P]α‐syn transgenic (A30P‐tg) mice. Our results reveal a previously undetected abundance of α‐syn oligomers in midbrain of young mice, whereas phosphorylated (pS129) and proteinase k‐resistant α‐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 α‐syn aggregation on brain tissue, from experimental mouse models in addition to post mortem PD cases.