Alpha-Synuclein transgenic Mouse Models
PD is a neurodegenerative disease characterized by loss of dopaminergic neurons in the mesencephalon and by progressive reduction of dopaminergic innervation of the dorsal striatum. Symptoms of PD are impairments of motor and cognitive functions, and vegetative disturbances. Among other findings, PD is associated with increased ubiquitination and with the accumulation of alpha-synuclein in Lewy bodies and dystrophic neurites.
These findings have led to the generation of several transgenic mouse models that express different isoforms of human alpha-synuclein under control of different promoters, in order to investigate pathological changes and test the efficacy of pharmaceutical compounds in preclinical drug development studies in vivo. Consequently, interference with aggregation of alpha-synuclein is a common target in the development of pharmaceutical approaches to prevent or ameliorate PD.
QPS Neuropharmacology has a license to Patent Rights owned by the Regents of the University of California for providing commercial testing services with two human alpha-synuclein transgenic mouse lines developed by Dr. Eliezer Masliah of UCSD. The alpha-synuclein transgenic mouse lines available at QPS Neuropharmacology feature different cellular expression patterns of human alpha-synuclein, age at onset and progression of pathology. These animals constitute suitable models to study the influence of drugs on alpha-synuclein-related brain pathology and behavior.
D-Line transgenic Mouse Model
This transgenic mouse line overexpresses wild type human alpha-synuclein under the regulatory control of the human platelet-derived growth factor–β (PDGF-β) promoter (D-line; Masliah et al. 2000, Science 287: 1265-9). Mice are bred on a C57BL/6 background. These mice replicate features of human synucleinopathies such as abnormal accumulation of alpha-synuclein, increased phosphorylation of alpha-synuclein and high levels of ubiquitin in cortical and subcortical regions of the brain. The distinct histopathological features of these animals allow testing the efficacy of pharmaceutical compounds to interfere with, or even reverse the progression of alpha-synuclein accumulation. Additional immunoreactivity occurs in presynaptic cortical terminals, consistent with its role as a presynaptic protein.
Figure: Quantitative immunofluorescence (A) reveals increases in human α-synuclein expression over age in D-Line mice in both neocortex and hippocampus. n = 10-12; Mean + SEM. Two-way ANOVA with Bonferroni’s post hoc test. *p<0.05; **p<0.01; ***p<0.001. B: Immunolabeling of phosphorylated human α-syn (red) in the hippocampal CA3 (A) and somatosensory cortex (B) of 7 month old D-Line mice. Phosphorylated human α-syn (red) is targeted to somata of principal neurons in the hippocampal stratum pyramidale (sp) where it accumulates in the nucleus (arrowheads), but is undetectable in neurites. Expression levels in the neocortex are shown in deep layers V and VI close to the white matter (wm). The green channel shows expression of transgenic human α-syn.
Line 61 transgenic Mouse Model
This transgenic mouse model overexpresses wild type human α-synuclein under the regulatory control of the murine Thy 1 promoter. The cellular expression is more widespread compared to the D-Line model, featuring high human α-synuclein mRNA levels in most brain areas. Line 61 mice show abnormal accumulation of human α-synuclein protein in cortical and subcortical regions of the brain, including the substantia nigra. Immunoreactivity is present in both neuronal somata and presynaptic terminals.
Overall expression levels are therefore higher compared to D-Line mice. The Line 61 mouse model is thus well-suited for studies that aim to reduce overall levels of human α-synuclein. Measurable behavioral differences to non-transgenic littermates start at about 2-4 month of age, depending on the behavioral test.
Figure 1: Motor deficits in Line 61 transgenic mice compared to age matched non-transgenic (ntg) littermates. A: Rota Rod of 1 – 6 month old Line 61 mice. B: Pasta gnawing test of 2 – 6 month old Line 61 mice. n = 10-15. Man + SEM; Two-way ANOVA with Bonferroni`s post hoc test. *p<0.05; **p<0.01; ***p<0.001.
Figure 2: Quantification of astrocytosis in Line 61 mice. A: GFAP immunoreactive (IR) area in percent was quantified in the striatum of 6, 9, and 12 month old Line 61 mice and non-transgenic (ntg) littermates. n = 4 per group. Mean + SEM; Two-way ANOVA with Bonferroni‘s post hoc test. *p<0.05. B: Representative images of GFAP labeling in the striatum of 6 month old Line 61 and ntg animals. Scale bar: 50 µm.
QPS Neuropharmacology offers a custom tailored study design for these models and we are flexible to accommodate to your special interests. We are also happy to advice you and propose study designs. QPS Neuropharmacology maintains its own colonies directly in our research facility. Non-transgenic littermates are available as control animals needed for proper study design.
We would be happy to test your compounds in these mouse models! Readouts depend on model but the most common are:
- α-synuclein levels and aggregates
- Phosphorylated α-synuclein
- Motor deficits
- Synaptic loss
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QPS Neuropharmacology is also ready to provide samples (brain tissue, CSF etc.) from these animals for analyses in your laboratory.
We are happy to receive your inquiry.