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. On average, they are heavier than wild-type mice at five months of age (Kelm-Nelson et al., 2018). Neuropathologically, these mice are grossly normal. However, behavioral deficits emerged at an early age.
PINK1 KO mice showed reduced spontaneous locomotor activity at three to six months of age as assessed by the number of steps, rears, and landings in the cylinder test. They also took longer than wild-type mice to turn and climb down a pole, a test of locomotor skill. Moreover, modest deficits in ultrasonic vocalizations were observed at four to six months of age (Kelm-Nelson et al., 2018).
Despite these behavioral alterations, the number of dopaminergic neurons in the substantia nigra and the levels of striatal dopamine at two to three months of age, as well as at eight to nine months of age, were comparable to those of wildtype mice. The morphology of dopaminergic neurons also appeared to be grossly intact (Kitada et al., 2007), and there was no reduction in tyrosine hydroxylase immunolabeling (Kelm-Nelson et al., 2018). Likewise, homozygotes and controls had comparable levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).
However, 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 cortico-striatal pathway. High frequency stimulation in the absence of magnesium elicited weaker long-term potentiation in medium spiny neurons from KO mice compared to those of wildtype mice. Moreover, high-frequency stimulation in the presence of magnesium failed to evoke long-term depression. 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).
Moreover, dendritic health appears to be affected in PINK1 KO mice. The dendrites of midbrain dopaminergic neurons from 10-month-old KOs were shorter than those of wild-type mice. Also, the dendrites of cultured cortical neurons isolated from embryonic mice grew more slowly, and harbored shorter mitochondria that occupied less dendritic volume and traveled less distance anterogradely. These alterations were accompanied by deficits in mitochondrial protein kinase A signaling, as suggested by reduced phosphorylation of the enzyme’s regulatory subunit β (DasBanerjee et al., 2017).
Cytokine levels in PINK1 KO mice serum were similar to those in wild-type mice, a surprising finding given the role PINK1 plays in mitophagy which, by removing damaged mitochondria, mitigates inflammatory responses. However, following exhaustive exercise, which acutely stresses mitochondria, cytokine concentrations shot up in the serum of KO, but not wild-type, mice (Sliter et al., 2018).
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
- Neuronal Loss
- Non-Motor Impairment
- α-synuclein Inclusions
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.
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.
Altered shape, density, and movement of dendritic mitochondria were observed in cultured primary neurons from embryonic mice. Also, an abnormal rise in serum cytokines in response to acute mitochondrial stress was reported in vivo.
Reduced spontaneous locomotor activity and skill reported at 3-6 months, as well as modest vocalization deficits at 4-6 months.
Last Updated: 11 Feb 2019
- 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.
- Kelm-Nelson CA, Brauer AF, Barth KJ, Lake JM, Sinnen ML, Stehula FJ, Muslu C, Marongiu R, Kaplitt MG, Ciucci MR. Characterization of early-onset motor deficits in the Pink1-/- mouse model of Parkinson disease. Brain Res. 2018 Feb 1;1680:1-12. Epub 2017 Dec 8 PubMed.
- Das Banerjee T, Dagda RY, Dagda M, Chu CT, Rice M, Vazquez-Mayorga E, Dagda RK. PINK1 regulates mitochondrial trafficking in dendrites of cortical neurons through mitochondrial PKA. J Neurochem. 2017 Aug;142(4):545-559. Epub 2017 Jun 23 PubMed.
- Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ. Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018 Sep;561(7722):258-262. Epub 2018 Aug 22 PubMed.
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