Progressive behavioral deficits in DJ-1-deficient mice are associated with normal nigrostriatal function
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disease with clinical features of resting tremor, rigidity and bradykinesia and pathological hallmarks of depletion of dopaminergic neurons in the substantia nigra and formation of intraneuronal Lewy bodies (Dauer and Przedborski, 2003). Although the majority of cases are sporadic, dominantly inherited mutations in α-synuclein and LRRK2 and recessively inherited mutations in parkin, DJ-1 and PINK1 have been linked to rare familial forms of PD. DJ-1-associated PD likely manifests via a loss-of-function mechanism as the first reported mutations were either a large genomic deletion resulting in an absence of protein and mRNA or an L166P missense mutation that resulted in rapid protein degradation (Bonifati et al., 2003, Miller et al., 2003). The presence of DJ-1 protein within tau inclusions in postmortem tissue taken from patients diagnosed with tauopathies suggests that DJ-1 loss may lead to a heterogenous catalogue of behavioral dysfunctions (Rizzu et al., 2004).
Four independent reports using different lines of DJ-1 knockout (DJ-1−/−) mice have suggested novel roles for DJ-1 in the modulation of dopaminergic neurons. DJ-1−/− mice were hypoactive in the open field, more susceptible to neuronal death from treatment of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), contained lower levels of presynaptic dopamine transporter (DAT) and had impaired dopamine receptor D2-mediated activities and long-term depression (LTD) in acute striatal slices (Chen et al., 2005, Goldberg et al., 2005, Kim et al., 2005, Manning-Bog et al., 2007). These reports, however, are not entirely consistent with each other regarding either behavioral dysfunction or dopaminergic transmission and only include data on the mice up to 12 months of age. A single recent report on aged DJ-1 mouse cohorts suggests that, with the exception of hypoactivity, no changes in basic motor activity are present in DJ-1−/− animals, and nigral pathology is normal (Yamaguchi and Shen, 2007).
To clarify the role of DJ-1 in neurotransmission and to identify any pathways linking the protein to PD, we generated DJ-1−/− mice by deleting the first coding exon (exon 2) and characterized the behavior and pathology until end stage (28 months). We chose behavioral paradigms suited to detecting alterations in both motor and dopaminergic function (Fleming and Chesselet, 2006) and extended previous studies by examining dopaminergic transmission in vivo using microdialysis. In addition to DJ-1−/− mice, other mouse models generated with genetic manipulations in parkin and α-synuclein have identified behavioral deficits consistent with alterations in the nigrostriatal pathway without accompanying nigral cell loss (Fleming et al., 2004, Goldberg et al., 2003). We now report that DJ-1 deficiency leads to progressive motor deficits without any obvious pathological changes in either the nigrostriatal system or spinal motor system and muscles.
Section snippets
Generation of DJ-1−/− mice
DNA fragments spanning exons 1–7 of DJ-1 were isolated from a mouse genomic phage library (Stratagene, CA). Targeting vectors were constructed through replacement of the second exon of DJ-1 with a neomycin resistance gene. The neomycin resistance gene was flanked by a 1.7-kb EcoRI–BamHI left arm fragment and a 5.0-kb right arm consisting of a 3.3-kb NheI–EcoRI fragment joined to a 1.7-kb EcoRI–SacI fragment. Linearized targeting vector was transfected by electroporation into mouse ES cells
Generation of DJ-1−/− mice
Targeted deletion of mouse DJ-1 was accomplished by replacing exon 2 with a neomycin resistance gene cassette (Supplementary Fig. 1A). Successful homologous recombination of the targeted exon 2 disruption was confirmed by Southern blot (Supplementary Fig. 1B) and Western blot (Supplementary Fig. 1C).
DJ-1−/− mice are hypoactive and display gait abnormalities
All offspring from DJ-1 heterozygous mating were viable, fertile and lacked obvious developmental abnormalities. From birth until 12 months, there were no significant differences in body weights
Discussion
Recessive mutations in DJ-1 are a rare cause of early-onset Parkinson's disease. To better understand the role the predicted loss of DJ-1 contributes to the pathophysiology of disease, we generated DJ-1 knockout (DJ-1−/−) mice and observed behavioral and pathological changes over the entire lifespan of the mice. We have demonstrated that DJ-1−/− mice develop progressive behavioral abnormalities in gaits and forearm grip strength and are hypoactive at both juvenile and adult ages.
Previously,
Acknowledgments
This work is supported by the intramural programs of the National Institute on Aging, the National Institute of Drug Abuse and the National Institute of Mental Health. We thank the Transgenic Core Facility of the Johns Hopkins University School of Medicine for the blastocyst injection.
References (45)
Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system
Neurobiol. Dis.
(2006)Quantitative no-net-flux microdialysis permits detection of increases and decreases in dopamine uptake in mouse nucleus accumbens
J. Neurosci. Methods
(2006)Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice
J. Biol. Chem.
(2005)Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases
J. Biol. Chem.
(2006)- et al.
Parkinson's disease: mechanisms and models
Neuron.
(2003) Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation
Mol. Cell. Neurosci.
(2003)Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons
J. Biol. Chem.
(2003)Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1
Neuron.
(2005)Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice
Neurobiol. Aging
(2003)Gait dynamics in trisomic mice: quantitative neurological traits of Down syndrome
Physiol. Behav.
(2004)
Age-dependent dopaminergic dysfunction in Nurr1 knockout mice
Exp. Neurol.
Rotorod sensorimotor learning in cerebellar mutant mice
Neurosci. Res.
Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter
Neurobiol. Dis.
Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion
J. Neurosci. Methods
Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress
Curr. Biol.
Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease
Curr. Biol.
L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system
J. Biol. Chem.
Mitochondrial dysfunction and oxidative damage in parkin-deficient mice
J. Biol. Chem.
Drosophila DJ-1 mutants show oxidative stress-sensitive locomotive dysfunction
Gene
Enhanced sensitivity of DJ-1-deficient dopaminergic neurons to energy metabolism impairment: role of Na+/K+ ATPase
Neurobiol. Dis.
An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria
Neuron.
Gait dynamics in mouse models of Parkinson's disease and Huntington's disease
J. Neuroengineering Rehabil.
Cited by (87)
DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis
2023, Neurobiology of DiseaseOxidative stress and synaptic dysfunction in rodent models of Parkinson's disease
2022, Neurobiology of DiseaseCitation Excerpt :To explore the role of DJ-1 in the dopaminergic system, a DJ-1 deficient mouse model was generated. DJ-1−/− mice showed decreased body weight gain, decreased grip strength and progressive gait abnormalities compared to wild-type littermates, although selective dopaminergic cell death was absent (Chandran et al., 2008). They showed reduction in evoked dopamine overflow in striatal slices, primarily due to increased dopamine reuptake.
The three sisters of fate: Genetics, pathophysiology and outcomes of animal models of neurodegenerative diseases
2022, Neuroscience and Biobehavioral ReviewsOligonucleotides as therapeutic tools for brain disorders: Focus on major depressive disorder and Parkinson's disease
2021, Pharmacology and TherapeuticsDJ-1 in neurodegenerative diseases: Pathogenesis and clinical application
2021, Progress in NeurobiologyMitophagy in Parkinson's disease: From pathogenesis to treatment target
2020, Neurochemistry International
- 1
Current address: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.