Genes: PRKN (parkin)
Mutations: Parkin Q311X
Modification: PRKN (parkin): Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: FVB/NJ-Tg(Slc6a3-PARK2*Q311X)AXwy/J
Genetic Background: The BAC was microinjected into fertilized FVB/NJ zygotes, then bred to FVB/NJ inbred mice.
Availability: Available through The Jackson Laboratory, Stock# 009090, Live.
This transgenic model of Parkinson’s disease expresses near-physiological levels of mutant parkin in dopaminergic neurons. The Q311X mutation is a nonsense mutation, which produces C-terminally truncated parkin, just 155 amino acids long. Notably, as they age, hemizygous mice lose dopaminergic neurons and develop progressive changes in motor behavior, including lower activity levels (Lu et al., 2009).
Parkin-Q311X mice have two copies of the transgene integrated in tandem. Expression levels of mutant parkin are fairly low in hemizygous mice, about 40 percent of endogenous murine levels. Transgenic mRNA was confirmed within dopaminergic neurons of the substantia nigra (SN) and ventral tegmental area (VTA) by in situ hybridization. Transgenic protein was observed in neurons co-staining with SLC6a3, a marker of dopaminergic neurons.
As they age, the mice lose dopaminergic neurons in the SN. The number of nigral neurons staining positive for tyrosine hydroxylase (TH) was comparable to wild-type mice at three months of age, but reduced by about 40 percent by 16 months of age. This decrease was primarily due to a drop in neuronal numbers, but also reflected reduced TH expression in the remaining neurons. Not surprisingly, the striatum received fewer dopaminergic projections and contained less dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), a dopamine metabolite. Neurons in the VTA were relatively spared.
Although Parkin-Q311X mice do not develop Lewy body-like inclusions, they do accumulate cytoplasmic α-synuclein in the midbrain. At three months of age the number of α-synuclein-positive nigral neurons was comparable to non-Tg, but it was elevated by 16 months. The cytoplasmic α -synuclin often co-localized with 3-nitrotyrosine, a marker of nitrative damage.
Hemizygous Parkin-Q311X mice behaved normally at young ages, but exhibited lower levels of activity as they aged and had other modest differences in locomotor behavior compared with non-Tg littermates. In the open-field test, both males and females exhibited hypoactivity at 16 and 21 months of age, but not at six and 12 months of age. They also exhibited deficits in the adhesive-removal test (which measures motor response to sensory stimuli) at 13 to 16 months. Motor behavior was studied in both male and female hemizygous mice and no significant sex differences were reported.
Bacterial artificial chromosome (BAC)-mediated expression of mutant parkin in dopaminergic neurons. The promoter and regulatory regions of Slc6a3 (dopamine transporter) drive expression of parkin with the truncation mutation Q311X. The protein has an N-terminal Flag-tag. Two copies of the transgene integrated in tandem.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- α-synuclein Inclusions
- Mitochondrial Abnormalities
- Cognitive Dysfunction
Inclusions were not observed at any age, however, the mice exhibit age-dependent accumulation of proteinase-K resistant endogenous α-synuclein in the substantia nigra.
Surviving nigral neurons had reduced tyrosine hydroxylase expression. By 19-21 months, striatal concentrations of dopamine and the dopamine metabolite, 3,4-dihydrooxyphenylacetic acid (DOPAC), were decreased compared with non-Tg littermates.
Behavior was fairly normal at 3 months, but motor abnormalities were measured by 16 months of age, including hypoactivity and deficits in coordination and in motor response to sensory stimuli.
Progressive loss of dopaminergic neurons in the substantia nigra. About 40 percent loss by 16 months of age with a corresponding decrease in dopaminergic projections to the striatum. Neurons in the ventral tegmental area were relatively spared.
- Lu XH, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, Hernandez D, Sulzer D, Jackson GR, Maidment NT, Chesselet MF, Yang XW. Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J Neurosci. 2009 Feb 18;29(7):1962-76. PubMed.
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