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

Autor: Moceri S; Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Bäuerle N; Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Habermeyer J; Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Ratz-Wirsching V; Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Harrer J; Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Distler J; Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Schulze-Krebs A; Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Timotius IK; Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; Department of Electronic Engineering, Satya Wacana Christian University, 50711 Salatiga, Indonesia., Bluhm A; Paul-Flechsig-Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany., Hartlage-Rübsamen M; Paul-Flechsig-Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany., Roßner S; Paul-Flechsig-Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany., Winkler J; Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany., Xiang W; Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany. Electronic address: wei.xiang@fau.de., Hörsten SV; Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany. Electronic address: stephan.v.hoersten@fau.de.
Jazyk: angličtina
Zdroj: Behavioural brain research [Behav Brain Res] 2024 Mar 05; Vol. 460, pp. 114781. Date of Electronic Publication: 2023 Dec 02.
DOI: 10.1016/j.bbr.2023.114781
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest We have no conflicts of interest to declare.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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