| First Author | Martinez Hernandez A | Year | 2021 |
| Journal | Front Neurosci | Volume | 15 |
| Pages | 643391 | PubMed ID | 34220415 |
| Mgi Jnum | J:314280 | Mgi Id | MGI:6729409 |
| Doi | 10.3389/fnins.2021.643391 | Citation | Martinez Hernandez A, et al. (2021) Low-Expressing Synucleinopathy Mouse Models Based on Oligomer-Forming Mutations and C-Terminal Truncation of alpha-Synuclein. Front Neurosci 15:643391 |
| abstractText | alpha-synuclein (alphaSyn) is the main protein component of Lewy bodies, intracellular inclusions found in the brain of Parkinson's disease (PD) patients. Neurotoxic alphaSyn 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 alphaSyn oligomerization and fibrillization. Although several genetic mouse models based on alphaSyn 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 alphaSyn, but do not overexpress the mutant protein when compared to the endogenous mouse protein. We knocked halphaSyn (TP) or halphaSyn(Delta119) (h stands for "human") into the murine alphaSyn locus. halphaSyn(TP) is a structure-based mutant with triple alanine to proline substitutions that favors oligomers, is neurotoxic and evokes PD-like symptoms in Drosophila melanogaster. halphaSyn(Delta119) lacks 21 amino acids at the C-terminus, favors fibrillary aggregates and occurs in PD. Knocking-in of halphaSyn (TP) or halphaSyn(Delta119) into the murine alphaSyn locus places the mutant protein under the control of the endogenous regulatory elements while simultaneously disrupting the malphaSyn gene. Mass spectrometry revealed that halphaSyn (TP) and halphaSyn(Delta119) mice produced 12 and 10 times less mutant protein, compared to malphaSyn in wild type mice. We show phenotypes in 1 and 1.5 years old halphaSyn (TP) and halphaSyn(Delta119) mice, despite the lower levels of halphaSyn(TP) and halphaSyn(Delta119) 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 halphaSyn(Delta119) mice, while a compulsive behavior was exclusively detected in halphaSyn (TP) mice starting at 1 year of age. We conclude that even at very moderate levels of expression the two alphaSyn variants evoke measurable and progressive deficiencies in mutant mice. The two transgenic mouse models can thus be suitable to study alphaSyn-variant-based pathology in vivo and test new therapeutic approaches. |
