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 over-
expressing 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 hy-
droxylase 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 expen-
diture 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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:94161 |
| Date | 21 October 2024 |
| Creators | Moceri, Sandra, Bäuerle, Natascha, Habermeyer, Johanna, Ratz-Wirsching, Veronika, Harrer, Julia, Distler, Jörg, Schulze-Krebs, Anja, Timotius, Ivanna K., Bluhm, Alexandra, Hartlage-Rübsamen, Maike, Roßner, Steffen, Winkler, Jürgen, Xiang, Wei, Hörsten, Stephan von |
| Publisher | Elsevier |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 114781, https://doi.org/10.1016/j.bbr.2023.114781 |
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