Behavioral Deficits and Brain α-Synuclein and Phosphorylated Serine-129 α-Synuclein in Male and Female Mice Overexpressing Human α-Synuclein

Background: Alpha-synuclein (alpha-syn) is involved in pathology of Parkinson's disease, and 90% of alpha-syn in Lewy bodies is phosphorylated at serine 129 (pS129 alpha-syn). Objective: To assess behavior impairments and brain levels of alpha-syn and pS129 alpha-syn in mice overexpressing human alpha-syn under Thy1 promoter (Thy1-alpha-syn) and wild type (wt) littermates. Methods: Motor and non-motor behaviors were monitored, brain human alpha-syn levels measured by ELISA, and alpha-syn and pS129 alpha-syn mapped by immunohistochemistry. Results: Male and female wt littermates did not show differences in the behavioral tests. Male Thy1-alpha-syn mice displayed more severe impairments than female counterparts in cotton nesting, pole tests, adhesive removal, finding buried food, and marble burying. Concentrations of human alpha-syn in the olfactory regions, cortex, nigrostriatal system, and dorsal medulla were significantly increased in Thy1-alpha-syn mice, higher in males than females Immunoreactivity of alpha-syn was not simply increased in Thy1-alpha-syn mice but had altered localization in somas and fibers in a few brain areas. Abundant pS129 alpha-syn existed in many brain areas of Thy1-alpha-syn mice, while there was none or only a small amount in a few brain regions of wt mice. The substantia nigra, olfactory regions, amygdala, lateral parabrachial nucleus, and dorsal vagal complex displayed different distribution patterns between wt and transgenic mice, but not between sexes. Conclusion: The severer abnormal behaviors in male than female Thy1-alpha-syn mice may be related to higher brain levels of human alpha-syn, in the absence of sex differences in the altered brain immunoreactivity patterns of alpha-syn and pS129 alpha-syn.

Automated summary

The study found that male Thy1-alpha-syn mice exhibited more severe behavioral impairments compared to their female counterparts, as well as wild type mice. The differences in behavior were related to higher brain levels of human alpha-syn, rather than sex differences in the altered brain immunoreactivity patterns of alpha-syn and pS129 alpha-syn.