PARK7 Mouse
Description
Genetic Characteristics of PARK7 Mouse Models
PARK7 knockout mice are engineered through targeted deletion of exon 2–4 of the Park7 gene, resulting in complete loss of DJ-1 protein expression . Key features include:
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Homology: 92% amino acid identity between human and mouse PARK7 .
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Expression: Ubiquitous, with high levels in the brain, kidneys, and testes .
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Phenotype: Age-dependent motor deficits, dopaminergic neuron vulnerability, and increased sensitivity to oxidative stress .
Metabolic Regulation
PARK7 prevents damage from glycolytic intermediates:
Loss of PARK7 leads to accumulation of damaged metabolites (e.g., N-glyceroyl-glutamate) in brain and peripheral tissues .
Neurodegenerative Phenotypes
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Motor deficits: Hypokinesia and impaired coordination manifest by 8–12 months .
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Dopaminergic system: Reduced tyrosine hydroxylase expression in substantia nigra (40% loss by 18 months) .
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Pathology: No Lewy body formation, but increased α-synuclein aggregation susceptibility .
Sex-Specific Transcriptomic Changes
A 2024 study revealed sex-dependent effects in Park7 −/− mice:
| Parameter | Male Mice | Female Mice |
|---|---|---|
| Differential genes (8 months) | 1,214 upregulated, 987 downregulated | No significant changes |
| Key pathways | NRF2 signaling, estrogen metabolism, EMT | Unaffected |
| Astrocyte dysfunction | CYP1B1 downregulation (linked to estrogen/retinoic acid metabolism) | Normal CYP1B1 levels |
Antibodies
Chemical Probes
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JYQ-92: Cyanimide inhibitor covalently targets Cys106; used for activity-based profiling .
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SulfoCy5 probe: Enables PARK7 inhibition assays in cell lysates .
Therapeutic Insights
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Metabolic intervention: Targeting 1,3-BPG metabolism may benefit PD patients with PARK7 mutations .
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NRF2 activation: Rescues antioxidant deficits in male Park7 −/− astrocytes .
Limitations and Controversies
Product Specs
Q&A
What is the PARK7 Gene and How Does It Relate to Parkinson's Disease?
The PARK7 gene encodes the DJ-1 protein, which functions as both a protein and nucleotide deglycase that catalyzes the deglycation of Maillard adducts formed between amino groups of proteins or nucleotides and reactive carbonyl groups of glyoxals . Loss-of-function mutations in PARK7 can lead to early-onset Parkinson's disease (PD) through multiple mechanisms .
DJ-1 serves critical protective functions including:
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Repairing methylglyoxal and glyoxal-glycated proteins
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Deglycating cysteine, arginine, and lysine residues in proteins
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Preventing formation of advanced glycation end products (AGEs)
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Repairing glycated guanine in the free nucleotide pool and in DNA/RNA
These functions highlight why DJ-1 deficiency contributes to neurodegeneration in PD, particularly through increased vulnerability to oxidative stress .
How Do PARK7 Knockout Mice Compare to Other PD Genetic Models?
PARK7 knockout mice exhibit distinct characteristics compared to other genetic PD models such as LRRK2 or Parkin knockout models. These differences are essential for researchers to consider when selecting appropriate models for specific research questions.
The variability in phenotypes across different PARK7 knockout studies can be attributed to factors including age at assessment, sex differences, genetic background, and experimental conditions . This variability highlights the importance of standardized protocols when working with these models.
What Are the Sex-Specific Transcriptomic Changes in PARK7 Knockout Mice?
Recent research has revealed striking sex-specific transcriptomic differences in PARK7 knockout mice that provide important insights into potential mechanisms of disease vulnerability:
At 3 months of age:
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No significant transcriptomic changes in either male or female Park7 knockout mice compared to wildtype littermates
At 8 months of age:
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Male Park7 knockout mice show extensive gene deregulation
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Female Park7 knockout mice maintain relatively normal transcriptomic profiles
The male-specific changes at 8 months affect genes involved in:
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Focal adhesion pathways
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Extracellular matrix interaction
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Epithelial-to-mesenchymal transition (EMT)
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Nuclear factor erythroid 2-related factor 2 (NRF2) target genes
Many of the misregulated genes are known targets of estrogen and retinoic acid signaling, which already show sex-specific expression patterns in wildtype mice. This suggests that loss of DJ-1 interferes with sex hormone-dependent gene regulation pathways, potentially explaining the male bias observed in certain aspects of PD pathology .
How Does PARK7 Deletion Affect the NRF2-CYP1B1 Axis in Astrocytes?
PARK7 deletion leads to significant disruption of the NRF2-CYP1B1 axis specifically in male astrocytes, creating a potential mechanism for sex-specific vulnerability to oxidative stress . This relationship can be characterized as follows:
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NRF2 pathway disruption:
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CYP1B1 downregulation:
These findings suggest that DJ-1's role extends beyond direct antioxidant functions to include regulation of sex hormone metabolism through the NRF2-CYP1B1 axis, which may explain the higher male susceptibility to certain aspects of PD pathology .
What Methodological Approaches Are Recommended for Studying Dopaminergic Deficits in PARK7 Mouse Models?
When investigating dopaminergic deficits in PARK7 knockout mice, researchers should implement a multi-modal approach that accounts for the age and sex-dependent nature of the phenotypes . Based on current literature, effective methodological approaches include:
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Transcriptomic analysis:
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Neurochemical assessments:
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Behavioral assessments:
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Histological and cellular analysis:
For optimal results, experimental designs should include longitudinal studies that track changes from early age (3 months) through middle age (8-12 months), with careful attention to sex as a biological variable .
What Critical Experimental Design Considerations Should Be Applied When Using PARK7 Mouse Models?
When designing experiments using PARK7 mouse models, researchers should consider several critical factors to ensure robust and reproducible results:
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Age considerations:
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Sex as a biological variable:
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Genetic background:
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Environmental factors:
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Challenge paradigms:
By carefully addressing these design considerations, researchers can maximize the translational value of studies using PARK7 mouse models and improve consistency across laboratories .
How Do Human iPSC Models with PARK7 Mutations Compare to PARK7 Mouse Models?
PARK7 mouse models and human iPSC models with PARK7 mutations offer complementary insights into DJ-1-related pathology:
| Feature | PARK7 Mouse Models | Human iPSC Models with PARK7 Mutations |
|---|---|---|
| Species relevance | Rodent biology may differ from human | Derived from human cells with human genetic background |
| System complexity | Complete in vivo system with intact brain circuitry | Limited to cell culture or organoid systems |
| Temporal scale | Can study aging effects over months/years | Limited to weeks/months in culture |
| Cell types | All brain cell types in natural proportions | Typically directed to specific lineages (neurons, astrocytes) |
| Sex-specific effects | Can study male vs. female differences | Sex-specific effects preserved in XX vs. XY lines |
| Key findings overlap | - NRF2 pathway dysregulation - Oxidative stress sensitivity - Mitochondrial dysfunction | - Similar molecular pathways affected - Similar vulnerability patterns |
Recent research shows that male iPSC-derived astrocytes with PARK7 loss-of-function mutations exhibit changes in the EMT pathway and NRF2 target genes similar to those observed in male PARK7 knockout mice, suggesting conservation of key molecular mechanisms between species .
For optimal translational research, combining insights from both model systems is recommended, using mouse models for in vivo, long-term studies while employing iPSC models for human-specific molecular mechanisms and personalized medicine approaches.
What CRISPR-Based Approaches Can Be Used to Create or Modify PARK7 Mouse Models?
CRISPR technology offers versatile approaches for creating and modifying PARK7 mouse models that extend beyond traditional knockout strategies:
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CRISPR/Cas9 knockout approaches:
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CRISPR activation (CRISPRa) applications:
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CRISPR interference (CRISPRi) strategies:
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Reversible repression of PARK7 expression
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Partial knockdown to model hypomorphic alleles
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Cell-type specific repression using tissue-specific promoters
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Knock-in approaches:
The OriGene mouse PARK7 activation kit exemplifies commercial tools available for CRISPR-based gene activation, containing three guide RNAs targeting the PARK7 gene along with enhancer and control vectors . These approaches extend the utility of PARK7 mouse models beyond simple knockouts to more sophisticated studies of gene dosage, cell-type specific functions, and precise modeling of human mutations.
Why Do Different PARK7 Knockout Mouse Studies Report Variable Phenotype Severity?
The variability in phenotypes observed across different PARK7 knockout studies can be attributed to several interacting factors:
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Age-dependent penetrance:
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Sex-specific mechanisms:
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Genetic background influences:
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Environmental and experimental variables:
The recent finding that DJ-1 loss leads to astrocytic alterations through the NRF2-CYP1B1 axis specifically in males helps explain some of this variability . Studies using mixed-sex cohorts or younger animals may miss these effects entirely, while studies focusing on aged male mice may detect stronger phenotypes.
What Are Optimal Methods for Assessing Oxidative Stress Responses in PARK7 Knockout Mice?
Given DJ-1's central role in oxidative stress protection, comprehensive assessment of redox status in PARK7 knockout mice requires multi-modal approaches:
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Biochemical markers of oxidative damage:
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Antioxidant system evaluation:
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Mitochondrial function assessment:
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Challenge paradigms:
For sex-specific studies, researchers should note that male PARK7 knockout mice show more pronounced deficits in antioxidant responses compared to females, particularly in the NRF2 pathway and downstream targets . Combining multiple measures across different biological scales provides the most comprehensive assessment of how DJ-1 deficiency alters oxidative stress responses.
Product Science Overview
PARK7 Mouse Recombinant is produced in E. coli as a single, non-glycosylated polypeptide chain containing 212 amino acids (1-189 a.a) and has a molecular mass of 22.4 kDa . The recombinant protein is fused to a 23 amino acid His-tag at the N-terminus, which facilitates its purification through chromatographic techniques .
DJ-1 exhibits several types of catalytic activity, including functioning as a protein deglycase (EC 3.5.1.124) . It acts as a positive regulator of androgen receptor-dependent transcription and may function as a redox-sensitive chaperone, sensing oxidative stress and protecting neurons against oxidative stress and cell death .
In different cellular compartments, DJ-1 exhibits both catalytic and non-catalytic functions. For instance, oxidative stress promotes the dissociation of cytoplasmic DJ-1 dimers into monomers, which are then translocated to the nucleus. In the nucleus, DJ-1 acts as a coactivator of various signaling pathways, preventing cell death . In mitochondria, DJ-1 is found in the synthasome, where it interacts with the β ATP synthase subunit .
Mutations in the DJ-1 gene (PARK7) are associated with autosomal recessive early-onset Parkinson’s disease (PD) . These mutations often result in impaired dimerization, stability, and folding of the protein, leading to its dysfunction . Downregulation of the DJ-1 gene increases the sensitivity of cells to neurotoxins, which is a characteristic feature of PD . Introduction of recombinant DJ-1 protein has been shown to attenuate the manifestation of PD pathology in experimental models .
The recombinant PARK7 protein is used in various research applications to study its role in neuroprotection and its potential therapeutic effects in PD models. It is also utilized in biochemical assays to understand its interaction with other proteins and its function under oxidative stress conditions .
