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

Article type: Research Article

Authors: Gabrielyan, Lilit^{a; 1} | Liang, Honghui^a | Minalyan, Artem^{a; 2} | Hatami, Asa^{b; 3} | John, Varghese^b | Wang, Lixin^{a; c; *}

Affiliations: [a] CURE/Digestive Disease Research Center, Med/Digestive, David Geffen Medical School, UCLA, Los Angeles, CA, USA | [b] Drug Discovery Lab, Department of Neurology, UCLA, Los Angeles, CA, USA | [c] VA Greater Los Angeles Health System, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Lixin Wang, PhD, 11301 Wilshire Blvd., Bldg. 115, Los Angeles, CA 90073, USA. Tel.: +1 310 478 3711/Ex 41831; E-mail: [email protected].

Note: [1] Present Address: University of Southern California, School of Pharmacy, Los Angeles, CA, USA

Note: [2] Present Address: Department of Medicine, Abington Hospital - Jefferson Health, Abington, PA, USA

Note: [3] Present Address: Sangamo Therapeutics, Richmond, CA, USA

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.

Keywords: α-synuclein, behavior, brain, mouse, phosphorylated serine-129 α-synuclein, synucleinopathy

DOI: 10.3233/JAD-200983

Journal: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 875-893, 2021