Alpha-Synuclein transgenic Mouse Models
PD is a neurodegenerative disease characterized by loss of dopaminergic neurons in the mesencephalon and by progressing 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 Austria 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 Austria 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
Strong immunoreactivity of human alpha-synuclein protein is evident in different subsets of neuronal somata in the above-mentioned areas, and both expression and aggregation of alpha-synuclein increase over age (Amschl et al. 2013, BMC Neurosci 9;14:6). This distinct histopathological pattern allows 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 (top) reveals increases in human α-synuclein expression over age in D-Line mice in both neocortex and hippocampus. Double immunofluorescence labeling (bottom) shows human α-synuclein expression in a subset of NeuN-positive pyramidal neurons in the hippocampus (left), co-immunoreactivity with phosphorylated α-synuclein (middle), and strong ubiquitin expression in D-Line mice (right).
Line 61 (TNWT61) transgenic Mouse Model
Overall expression levels are therefore higher compared to D-Line mice; however, the expression in individual neurons is moderate, avoiding common problems (e.g. cytotoxicity) associated with massive overproduction of transgenic protein when excessively strong promoters are used. The Line 61 mouse model is therefore well suited for studies that aim to reduce overall levels of human alpha-synuclein. Measurable behavioral differences to non-transgenic littermates start at about 2-4 four months of age, depending on the behavioral test (Fleming et al. 2004, J Neurosci 24: 9434-40).
Figure: Results from the challenging beam walk and the pole test indicate impaired motor function in Line 61 (TNWT61) mice compared to wildtype mice (t-test). Double immunofluorescence labeling shows strong human alpha-synuclein expression in a large number of NeuN-positive pyramidal neurons in the hippocampus (HC). Campbell-Switzer silver stains show aggregation of synuclein in somata and neuropil in the substantia nigra (SN).
- Motor function (Rotarod, Beam Walk)
- Murine, human, and phosphorylated alpha-synuclein in brain extracts or in immunohistology
- Integrity of the striatum and dopaminergic system (TH, DAT, DARPP-32, ChAT)
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As with all other in vivo models we are also ready to provide samples (brain tissue, CSF etc.) from these animals for analyses in your laboratory. We are happy to receive your inquiry.