Young human alpha synuclein transgenic (BAC-SNCA) mice display sex- and gene-dose-dependent phenotypic disturbances

Moceri S, Bäuerle N, Habermeyer J, Ratz-Wirsching V, Harrer J, Distler J, Schulze-Krebs A, Timotius IK, Bluhm A, Hartlage-Rübsamen M, Roßner S, Winkler J, Xiang W, von Hörsten S (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Behavioural Brain Research Elsevier

Book Volume: 460

Article Number: 114781

DOI: 10.1016/j.bbr.2023.114781

Abstract

Parkinson's disease (PD) is a common neurodegenerative movement disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of aggregated alpha synuclein (aSyn). The disease often presents with early prodromal non-motor symptoms and later motor symptoms. Diagnosing PD based purely on motor symptoms is often too late for successful intervention, as a significant neuronal loss has already occurred. Furthermore, the lower prevalence of PD in females is not well understood, highlighting the need for a better understanding of the interaction between sex and aSyn, the crucial protein for PD pathogenesis. Here, we conducted a comprehensive phenotyping study in 1- to 5-month-old mice overexpressing human aSyn gene (SNCA) in a bacterial artificial chromosome (BAC-SNCA). We demonstrate a SNCA gene-dose-dependent increase of human aSyn and phosphorylated aSyn, as well as a decrease in tyrosine hydroxylase expression in BAC-SNCA mice, with more pronounced effects in male mice. Phosphorylated aSyn was already found in the dorsal motor nucleus of the vagus nerve of 2-month-old mice. This was time-wise associated with significant gait altrations in BAC-SNCA mice as early as 1 and 3 months of age using CatWalk gait analysis. Furthermore, anxiety-related behavioral tests revealed an increase in anxiety levels in male BAC-SNCA mice. Finally, 5-month-old male BAC-SNCA mice exhibited a SNCA gene-dose-dependent elevation in energy expenditure in automated home-cage monitoring. For the first time, these findings describe early-onset, sex- and gene-dose-dependent, aSyn-mediated disturbances in BAC-SNCA mice, providing a model for sex-differences, early-onset neuropathology, and prodromal symptoms of PD.

Authors with CRIS profile

Sandra Moceri Department of Experimental Therapy Johanna Habermeyer Department of Experimental Therapy Veronika Ratz-Wirsching Department of Experimental Therapy Jörg Distler Medizinische Fakultät Jürgen Winkler Professur für Molekulare Neurologie Wei Xiang Department of Molecular Neurology Stephan von Hörsten Professur für Experimentelle Biomedizin

Involved external institutions

Universität Leipzig DE Germany (DE)

How to cite

APA:

Moceri, S., Bäuerle, N., Habermeyer, J., Ratz-Wirsching, V., Harrer, J., Distler, J.,... von Hörsten, S. (2024). Young human alpha synuclein transgenic (BAC-SNCA) mice display sex- and gene-dose-dependent phenotypic disturbances. Behavioural Brain Research, 460. https://dx.doi.org/10.1016/j.bbr.2023.114781

MLA:

Moceri, Sandra, et al. "Young human alpha synuclein transgenic (BAC-SNCA) mice display sex- and gene-dose-dependent phenotypic disturbances." Behavioural Brain Research 460 (2024).

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