Modification: PINK1: Knock-Out
Disease Relevance: Parkinson's Disease
Strain Name: B6.129S4-Pink1tm1Shn/J
Genetic Background: Congenic C57BL/6J. The construct was introduced into 129S4/SvJae-derived J1 embryonic stem cells, which were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to generate homozygotes and then backcrossed to C57BL/6J for >7 generations.
Availability: Available through The Jackson Laboratory, Stock# 017946; Live.
This mouse model was developed to investigate the effects of PINK1 deficiency (Kitada et al., 2007). The model involves a germline deletion of exons 4-7 of the endogenous PINK1 gene, creating truncated transcripts that are degraded. Mice homozygous for the null allele lack observable PINK1 protein. Homozygous mice have normal numbers of dopaminergic neurons and levels of striatal dopamine. However, they exhibit decreased evoked release of dopamine and other changes in striatal dopaminergic physiology.
Homozygous mice are viable and fertile. Neuropathologically, these mice are grossly normal. They did not have dopaminergic neuron loss in the substantia nigra at two to three months of age, nor at eight to nine months of age. The morphology of dopaminergic neurons also appeared to be grossly intact.
Overall striatal levels of dopamine did not significantly differ from levels in wild-type mice at two to three months or eight to nine months of age. Likewise, homozygotes and controls had comparable levels of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).
Notably, striatal slices from homozygous mice exhibited reduced dopamine release in response to electrical stimulation. Reduced evoked catecholamine release was also observed in disassociated adrenal chromaffin cells.
The reduced transmission of dopamine was associated with plasticity abnormalities in the striatum. Medium spiny neurons showed reduced long-term potentiation (LTP) and absent long-term depression (LTD) in response to high-frequency stimulation. These impairments could be rescued by dopamine receptor agonists, suggesting dopamine receptors were functional. Quantitative analysis of dopamine binding in the striatum confirmed there was no difference in the density of D1 and D2 receptors (Kitada et al., 2007).
The behavior of these mice has not been reported.
A targeting vector containing a PGK-Neo cassette was used to disrupt exons 4 through 7 of the endogenous PINK1 gene. This creates a nonsense mutation at the beginning of exon 8; truncated RNA is degraded.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Dopamine Deficiency
- Mitochondrial Abnormalities
- Neuronal Loss
- α-synuclein Inclusions
- Motor Impairment
- Cognitive Dysfunction
Overall striatal levels of dopamine did not significantly differ from levels in wild-type mice at two to three months or eight to nine months of age.
No overt mitochondrial morphological defects.
No decrease in the number of dopaminergic neurons in the substantia nigra at 2-3 months or 8-9 months of age. Neuronal morphology also grossly intact.
- Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos EN, Shen J. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11441-6. PubMed.
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