Transmission of Prion Strains in a Transgenic Mouse Model Overexpressing Human A53T Mutated α-Synuclein

Abstract

There is a growing interest in the potential roles of misfolded protein interactions in neurodegeneration. To investigate this issue, we inoculated 3 prion strains intracerebrally into transgenic (TgM83) mice that overexpress human A53T α-synuclein. In comparison to nontransgenic controls, there was a striking decrease in the incubation periods of scrapie, classic and H-type bovine spongiform encephalopathies(C-BSE and H-BSE), with conservation of the histopathologic and biochemical features characterizing these 3 prion strains. TgM83 mice died of scrapie or C-BSE prion diseases before accumulating the insoluble and phosphorylated forms of α-synuclein specific to late stages of synucleinopathy. In contrast, the median incubation time for TgM83 mice inoculated with H-BSE was comparable to that observed when these mice were uninfected, thereby allowing the development of molecular alterations of α-synuclein. The last 4 mice of this cohort exhibited early accumulations of H-BSE prion protein along with α-synuclein pathology. The results indicate that a prion disease was triggered concomitantly with an overt synucleinopathy in some transgenic mice overexpressing human A53T α-synuclein after intracerebral inoculation with an H-BSE prion strain.

Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

“…Using the PET blot method, we demonstrated that this pathologic form of >-synuclein is also PK resistant in the brain as well as in the gut. Using a panel of mice aged 1.5 to 22 months, we showed that pSer129 >-synuclein is not detected in the brains of young mice, in accordance with earlier observations (23), or in the ENS. More surprisingly, from as early as 5.5 months and up to 22 months of age, every TgM83 mouse analyzed showed aggregates of pSer129 >-synuclein in the brain and in the ENS in contrast to absence of any labeling in C57Bl/6 and C57Bl/6S control mice.…”

“…Interestingly, diffuse perikaryal staining as well as spheroid-like inclusions in the enteric neurons were similar to those observed in neurons of the brains of this mouse model (21,23) and are comparable to those reported in enteric plexuses of PD patients (12,14,34Y36). Nevertheless, the labeling typically found in dystrophic neurites in the CNS was not easy to detect in the gut sections.…”

“…Aggregates of pSer129 >-synuclein were detected by IHC using a rabbit monoclonal antibody raised against human pSer129 >-synuclein (clone EP1536Y; Abcam, Cambridge, UK), according to a previously described protocol (23). Briefly, to enhance immunoreactivity of the pSer129 >-synuclein protein, sections were boiled in 0.1 mol/L citrate buffer (pH 6.2) for 5 minutes in a microwave oven.…”

Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification

“…Injection of pre-formed α-Syn fibrils assembled in vitro into the brains of Tg mice bearing human mutant Tau also was used to demonstrate cross-seeding from α-Syn to Tau in vivo [110]. In other experiments, the inoculation of mouse-adapted scrapie strains intracerebrally into Tg mice that overexpress human α-Syn [111] or injection of heterotypic Aβ-seeded Tau in Tg mice (TauP301S) [44] was applied to study the interactions between these proteins. The inoculation of mouse-adapted PrP Sc into aged α-Syn Tg mice was used to prove that PrP Sc could promote α-Syn pathology [112].…”

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

“…However, it is unclear to what extent they are self-propagating in a prion-like manner (220)(221)(222)(223)(224). In vivo studies of intracerebral injections of aggregated α-synuclein in transgene animal models with α-synuclein mutations have further shown accelerated occurrence of protein aggregation, followed by nigral loss and motor deficits, not present to the similar extent in wild type (WT) animals (225)(226)(227). Thus, exogenous seeds of α-synuclein may accelerate the pathogenesis of a genetically predisposed α-synuclein aggregation disease.…”