Low-Expressing Synucleinopathy Mouse Models Based on Oligomer-Forming Mutations and C-Terminal Truncation of α-Synuclein
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 substit...
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Published in | Frontiers in neuroscience Vol. 15; p. 643391 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
17.06.2021
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Subjects | |
Online Access | Get full text |
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Summary: | 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 h
αSyn
TP
or h
αSyn
Δ119
(h stands for “human”) into the murine
αSyn
locus. hαSyn
TP
is a structure-based mutant with
t
riple alanine to
p
roline substitutions that favors oligomers, is neurotoxic and evokes PD-like symptoms in
Drosophila melanogaster
. hαSyn
Δ119
lacks 21 amino acids at the C-terminus, favors fibrillary aggregates and occurs in PD. Knocking-in of h
αSyn
TP
or h
αSyn
Δ119
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 h
αSyn
TP
and h
αSyn
Δ119
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
hαSyn
TP
and
hαSyn
Δ119
mice, despite the lower levels of hαSyn
TP
and hαSyn
Δ119
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
hαSyn
Δ119
mice, while a compulsive behavior was exclusively detected in
hαSyn
TP
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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience Edited by: Cintia Roodveldt, Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER), Spain Reviewed by: Michal Wegrzynowicz, Mossakowski Medical Research Centre, Polish Academy of Sciences, Poland; Changyoun Kim, National Institute on Aging, National Institutes of Health (NIH), United States |
ISSN: | 1662-453X 1662-4548 1662-453X |
DOI: | 10.3389/fnins.2021.643391 |