Disease relevance of Park2

• Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease [1].
• Mutations of the Park-2 gene are the most frequent cause of familial parkinsonism and parkin knockout (PK-KO) mice have abnormalities that resemble the clinical syndrome [2].
• We used recombinant adeno-associated virus (AAV) gene transfer to study the influence of DJ-1 and Parkin on the dopaminergic system of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, a model for sporadic PD [3].
• As loss of function mutations of parkin are the principal cause of a familial Parkinson's disease, a prevailing hypothesis is that the loss of parkin activity results in accumulation of Septin 5 which confers neuron-specific toxicity in SN-DAergic neurons [4].
• However, in contrast to observations in neuroblastoma cells, we saw no up-regulation of parkin expression in primary neuronal cell cultures after induction of ER dysfunction [5].

Psychiatry related information on Park2

• Cinnarizine, a calcium antagonist that produces parkinsonism in humans, induces behavioural changes such as alopecia, buco-lingual dyskinesia and reduction of motor activity in female parkin knock out (PK-KO) mice but not in wild-type (WT) controls [6].

High impact information on Park2

• Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism [7].
• Therefore, parkin and alpha-synuclein are linked by common effects on a pathway associated with selective cell death in catecholaminergic neurons [8].
• Intriguingly, alpha-synuclein (alpha-SN), another familial Parkinson's disease (PD) gene product, abrogated the 14-3-3eta-induced suppression of parkin activity. alpha-SN could bind tightly to 14-3-3eta and consequently sequester it from the parkin-14-3-3eta complex [9].
• To determine whether mutations in the mouse parkin gene (Park2) also result in a parkinsonian phenotype, we generated mice with a targeted deletion of parkin exon 2 [10].
• Moreover, catecholamine levels in the striatum, olfactory bulb, and spinal cord of Parkin-deficient mice were normal [10].

Chemical compound and disease context of Park2

• Our data show that, contrary to the expectations, and related to the enhanced production of GSH in parkin knockout mice, parkin-deficient dopamine neurons are less susceptible to toxicity by NO [11].
• Effects of cinnarizine, a calcium antagonist that produces human parkinsonism, in parkin knock out mice [6].
• Here we show that stable transfection of parkin in the human dopaminergic neuroblastoma cell line SH-SY5Y markedly reduced the activities of both monoamine oxidase (MAO) A and B. The amount of 3,4-dihydroxyphenylacetic acid, which is produced during dopamine oxidation by MAO, was greatly reduced by parkin overexpression [12].
• We examined the effects of manganese on parkin, identified as the gene responsible for familial Parkinson's disease, and the role of parkin in manganese-induced neuronal cell death [13].
• Since Parkin is thought to protect against neurotoxic insults, we hypothesized that the reason Parkin-deficient mice do not develop parkinsonism is because they are not exposed to appropriate environmental triggers [14].

Biological context of Park2

• Parkin null mice have a mild phenotype that could be modified by different neurotoxins [15].
• Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function [16].
• Differential effects of l-DOPA on monoamine metabolism, cell survival and glutathione production in midbrain neuronal-enriched cultures from parkin knockout and wild-type mice [15].
• The quaking mutation is a deletion of approximately 1.17 Mb of mouse chromosome 17, resulting in the deletion of the entire promoter and first five coding exons of PRKN In addition, the recently described Parkin Co-Regulated Gene (PACRG) is completely deleted [17].
• Parkin-deficient animals exhibit mitochondrial degeneration and increased oxidative stress vulnerability, and both mice and flies lacking DJ-1 are hypersensitive to environmental toxins associated with Parkinson's disease (PD) [3].

Anatomical context of Park2

• The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease [1].
• Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy [18].
• Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin [18].
• Many sporadic PD patients have a defect in mitochondria respiration, and some of the genes that cause PD are mitochondrial-related (e.g., PINK1, Parkin, DJ1) [19].
• Cannabinoid CB(1) receptors in the basal ganglia and motor response to activation or blockade of these receptors in parkin-null mice [20].

Associations of Park2 with chemical compounds

• Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice [1].
• The levels of glutathione were further increased in parkin null mice than in controls both with and without treatment with l-DOPA, suggesting that a compensatory mechanism may protect DA neurones from neuronal death [15].
• Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline [2].
• Our results show that Parkin and DJ-1 inhibit dopamine neuron death and enhance amphetamine-induced dopaminergic function in a mouse model of idiopathic PD [3].
• These changes are associated with differences in behavioral responses to cannabinoid agonists or antagonists between Park-2 knockout and wild-type mice, although parkin-null mice exhibited evident gender-dependent differences for both levels of CB(1) receptors and motor responses to agonists or antagonists [20].

Other interactions of Park2

• It's a double knock-out! The quaking mouse is a spontaneous deletion of parkin and parkin co-regulated gene (PACRG) [17].
• We have identified the mouse mutant Quaking as a spontaneously occurring PRKN knockout [17].
• MPTP drastically reduced dopamine to 19% of normal levels and neither DJ-1 nor Parkin protected against MPTP-induced catecholamine loss under these conditions [3].
• Septin 5, a parkin substrate, is a vesicle- and membrane-associated protein that plays a significant role in inhibiting exocytosis [4].
• By contrast, the administration of the CB(1) receptor antagonist SR141716 resulted in a hyperkinetic response in parkin-null mice, response that was almost absent in wild-type animals and that was accompanied by a decrease in tyrosine hydroxylase activity in the caudate-putamen [20].

Analytical, diagnostic and therapeutic context of Park2

• The PK-KO mice, however, are not only resistant to the l-DOPA-induced pro-apoptotic effects but they have an increased number of TH-immunoreactive neurones after treatment with l-DOPA, suggesting that l-DOPA is toxic for neurones of WT mice but not those of parkin null mice [15].
• Animal models provide a useful tool for the study of development and disease, and the recent production of transgenic fly and mouse parkin deficient models allows investigation of the molecular role of parkin in dopamine regulation and nigrostriatal function [17].
• These results warrant further exploration of DJ-1 and Parkin gene therapy for PD, although a better understanding of their effects on behavior and dopamine neurotransmission is required before these proteins can be safely used.Molecular Therapy (2007) 15 4, 698-704. doi:10.1038/sj.mt.6300067 [3].
• Our data thus suggest that ischemia-induced depletion of parkin protein may contribute to the pathological process resulting in cell injury by increasing the sensitivity of neurons to ER dysfunction and the aggregation of ubiquitylated proteins during the reperfusion period [5].
• The antibodies were shown to be specific using Western blot analysis, immunostaining of cells transfected with mouse Parkin and pre-absorption tests [21].

References