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  Low-Expressing synucleinopathy mouse models based on oligomer-forming mutations and C-terminal truncation of α-synuclein

Martinez Hernandez, A., Silbern, I., Geffers, I., Tatenhorst, L., Becker, S., Urlaub, H., et al. (2021). Low-Expressing synucleinopathy mouse models based on oligomer-forming mutations and C-terminal truncation of α-synuclein. Frontiers in Neuroscience, 15: 643391. doi:10.3389/fnins.2021.643391.

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Martinez Hernandez, A.1, Author              
Silbern, I.2, Author              
Geffers, I.3, Author              
Tatenhorst, L., Author
Becker, S.4, Author              
Urlaub, H.5, Author              
Zweckstetter, M.6, Author              
Griesinger, C.4, Author              
Eichele, G.1, Author              
Affiliations:
1Department of Genes and Behavior, MPI for biophysical chemistry, Max Planck Society, ou_persistent34              
2Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              
3Department of Genes and Behavior, MPI for Biophysical Chemistry, Max Planck Society, ou_persistent34              
4Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
5Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              
6Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 Abstract: α-synuclein (αSyn) is the main protein component of Lewy bodies, intracellular inclusions found in the brain of Parkinson’s disease (PD) patients. Neurotoxic αSyn species are broadly modified post-translationally and, in patients with genetic forms of PD, carry genetically encoded amino acid substitutions. Mutations and C-terminal truncation can increase αSyn oligomerization and fibrillization. Although several genetic mouse models based on αSyn mutations and/or truncations exist, there is still a lack of mouse models for synucleinopathies not relying on overexpression. We report here two synucleinopathy mouse models, which are based on a triple alanine to proline mutation and a C-terminal truncation of αSyn, but do not overexpress the mutant protein when compared to the endogenous mouse protein. We knocked hαSynTP or hαSynΔ119 (h stands for “human”) into the murine αSyn locus. hαSynTP is a structure-based mutant with triple alanine to proline substitutions that favors oligomers, is neurotoxic and evokes PD-like symptoms in Drosophila melanogaster. hαSynΔ119 lacks 21 amino acids at the C-terminus, favors fibrillary aggregates and occurs in PD. Knocking-in of hαSynTP or hαSynΔ119 into the murine αSyn locus places the mutant protein under the control of the endogenous regulatory elements while simultaneously disrupting the mαSyn gene. Mass spectrometry revealed that hαSynTP and hαSynΔ119 mice produced 12 and 10 times less mutant protein, compared to mαSyn in wild type mice. We show phenotypes in 1 and 1.5 years old hαSynTP and hαSynΔ119 mice, despite the lower levels of hαSynTP and hαSynΔ119 expression. Direct comparison of the two mouse models revealed many commonalities but also aspects unique to each model. Commonalities included strong immunoactive state, impaired olfaction and motor coordination deficits. Neither model showed DAergic neuronal loss. Impaired climbing abilities at 1 year of age and a deviant gait pattern at 1.5 years old were specific for hαSynΔ119 mice, while a compulsive behavior was exclusively detected in hαSynTP mice starting at 1 year of age. We conclude that even at very moderate levels of expression the two αSyn variants evoke measurable and progressive deficiencies in mutant mice. The two transgenic mouse models can thus be suitable to study αSyn-variant-based pathology in vivo and test new therapeutic approaches.

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Language(s): eng - English
 Dates: 2021-06-17
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.3389/fnins.2021.643391
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Title: Frontiers in Neuroscience
Source Genre: Journal
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Pages: 17 Volume / Issue: 15 Sequence Number: 643391 Start / End Page: - Identifier: -