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

Abstract

Background: Alpha-synuclein (α-syn) is involved in pathology of Parkinson’s disease, and 90% of α-syn in Lewy bodies is phosphorylated at serine 129 (pS129 α-syn). Objective: To assess behavior impairments and brain levels of α-syn and pS129 α-syn in mice overexpressing human α-syn under Thy1 promoter (Thy1-α-syn) and wild type (wt) littermates. Methods: Motor and non-motor behaviors were monitored, brain human α-syn levels measured by ELISA, and α-syn and pS129 α-syn mapped by immunohistochemistry. Results: Male and female wt littermates did not show differences in the behavioral tests. Male Thy1-α-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 α-syn in the olfactory regions, cortex, nigrostriatal system, and dorsal medulla were significantly increased in Thy1-α-syn mice, higher in males than females. Immunoreactivity of α-syn was not simply increased in Thy1-α-syn mice but had altered localization in somas and fibers in a few brain areas. Abundant pS129 α-syn existed in many brain areas of Thy1-α-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-α-syn mice may be related to higher brain levels of human α-syn, in the absence of sex differences in the altered brain immunoreactivity patterns of α-syn and pS129 α-syn.

Neuronal Oxidative Stress Promotes α-Synuclein Aggregation In Vivo

“…Results of our behavioral assessments also correspond to prior studies using the hSyn mice [ 28 , 57 ]. On the pole test, turnaround time was greater in the hSyn/EAAT3 −/− than in the hSyn mice at both the four-month and eight-month time points, and this difference was further increased at the eight-month time point.…”

“…The hSyn mice carry the human α-synuclein transgene on the X chromosome (X hSyn ). We initially backcrossed these mice onto the C57BL/6 strain (Jackson Labs), but due to poor breeding on that background the mice were re-crossed with the DBA/2 parental strain to generate a colony on a 1:1 DBA/2: C57BL/6 background, as described previously [ 26 , 27 , 28 ]. EAAT3 −/− mice on the C57BL/6 background were then likewise crossed with DBA/2 mice to generate a colony on a 1:1 DBA/2: C57BL/6 background.…”

Alpha-Synuclein Post-translational Modifications: Implications for Pathogenesis of Lewy Body Disorders

“…Similarly, pSer 129 was found in post-mortem brain in LBDs subjects and in SH-SY5Y cells that overexpress wild-type aSyn (Swirski et al, 2014). A recent study demonstrated behavioral deficits associated to widespread pSer 129 aSyn in brains of wild-type d transgenic mice that overexpress aSyn under Thy1-promoter (Gabrielyan et al, 2021), as pSer 129 phospho-memetic reported slower/inhibited aggregation kinetic than wild-type aSyn, despite its prominence in LBs and the preferential phosphorylation of fibrillar aSyn. It has been, suggested that pSer 129 is a late-stage event in aggregation leading to the fibrillization of aSyn, and pSer 129 is deemed to be crucial for the regulation of disease progression (Paleologou et al, 2010;Waxman and Giasson, 2011;Wales et al, 2013).…”

Distinct patterns of gene expression changes in the colon and striatum of young mice overexpressing alpha-synuclein support Parkinson Disease as a multi-system process

“…Male mice are used because the transgene is located on the X chromosome, and female mice exhibit a variable phenotype likely due to random X inactivation. [15] The genotype of all mice was determined at 21 days and veri ed at the end of the study with polymerase chain reaction (PCR) ampli cation analysis of tail DNA. Animal care was conducted in accordance with the United States Public Health Service Guide for the Care and Use of Laboratory Animals, and procedures were approved by the Institutional Animal Care and Use Committee at the University of California Los Angeles (UCLA).…”