Absence of dopaminergic neuronal degeneration and oxidative damage in aged DJ-1-deficient mice
© Yamaguchi and Shen; licensee BioMed Central Ltd. 2007
Received: 10 April 2007
Accepted: 29 May 2007
Published: 29 May 2007
Parkinson's disease is the most common movement disorder characterized by dopaminergic dysfunction and degeneration. Loss-of-function mutations in the DJ-1 gene have been linked to autosomal recessive forms of early-onset familial Parkinson's disease. DJ-1 is thought to play roles in protection of cells against oxidative stress and in maintenance of the normal dopaminergic function in the nigrostriatal pathway. Here we investigate the consequence of both DJ-1 inactivation and aging in mice. We found that DJ-1-/- mice at the age of 24–27 months have normal numbers of dopaminergic neurons in the substantia nigra and normal levels of dopamine and its major metabolites in the striatum. The number of noradrenergic neurons in the locus coeruleus is also unchanged in DJ-1-/- mice. Moreover, there is no accumulation of oxidative damage or inclusion bodies in aged DJ-1-/- brains. Together, these results indicate that loss of DJ-1 function alone is insufficient to cause nigral degeneration and oxidative damage in the life span of mice.
Parkinson's disease (PD) is an age-related movement disorder characterized clinically by bradykinesia, rigidity, resting tremor and postural instability, and neuropathologically by the selective loss of dopaminergic (DA) neurons and the presence of Lewy bodies in the substantia nigra (SN). Although most PD cases are sporadic, mutations in parkin (PARK2), PINK1 (PARK6), and DJ-1 (PARK7) have been linked to recessively inherited forms of parkinsonism, which resemble idiopathic PD clinically [1–3]. To investigate how DJ-1 deficiency causes PD, we have previously generated a mouse model bearing a targeted germline disruption of DJ-1, and our multidisciplinary analysis has uncovered an essential role for DJ-1 in DA physiology and dopamine D2 receptor-mediated functions .
Besides the importance of DJ-1 in DA neurotransmission and signaling, DJ-1 has been reported to have multiple functions associated with PD pathogenesis. First, several cysteine residues in DJ-1 can be oxidized in response to oxidative stress, and wild-type but not mutant DJ-1 protects cells from oxidative stress [5–11]. Furthermore, DJ-1 has been shown to stabilize the antioxidant transcription master regulator Nrf2 (nuclear factor erythroid 2-related factor) . Second, DJ-1 has chaperone activity and inhibits α-synuclein aggregation, which is thought to be a key event in Lewy body formation . Third, it has been suggested that DJ-1 might be involved in transcriptional regulation of neuroprotective or anti-apoptotic genes .
DA neurons are likely to be exposed to increased levels of oxidative stress caused by the metabolic products of dopamine in comparison to other types of neurons in the brain. It is thought that reactive oxygen species (ROS) oxidizes lipids, proteins and nucleic acids, resulting in cellular dysfunction or death [15, 16]. Evidence has shown that products of lipid, protein and DNA oxidation accumulate in PD brains [17, 18]. It has been shown that levels of DJ-1 protein are significantly increased in PD brains and cerebrospinal fluids, and DJ-1 is oxidatively damaged in the brains of patients with sporadic PD [19–21]. Therefore, it has been hypothesized that DJ-1 plays a critical role in antioxidant mechanisms and preventing cellular dysfunction or death in DA neurons. Consistent with this notion, DJ-1 deficiency induces an increased sensitivity to oxidative stimuli, including hydrogen peroxide, 6-hydroxydopamine, and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), and overexpression DJ-1 protects neurons from various oxidative stimuli [5, 10, 22–25]. Furthermore, Drosophila DJ-1 mutants showed accumulation of ROS and are sensitive to oxidative stress including paraquat, rotenone or hydrogen peroxide [9, 26]. DJ-1-/- mice showed increased sensitivity to MPTP and oxidative stress . It however remains unclear whether DJ-1 deficiency would lead to accumulation of oxidative damage in aging mouse brains in the absence of environmental oxidative stressors.
Lewy bodies are protein aggregates containing α-synuclein and ubiquitin and are considered a pathological hallmark of PD. Therefore, we examined DJ-1-/- brains for deposits of α-synuclein and ubiquitin. Immunohistochemical analysis of DJ-1-/- brains using antibodies specific for α-synuclein and ubiquitin showed no inclusions in any brain sub-regions, including the SN at the age of 24–27 months (data not shown).
Mutations in parkin (PARK2), PINK1 (PARK6), and DJ-1 (PARK7) are associated with autosomal recessive PD, in which loss of function of each of these gene products leads to degeneration of DA neurons and clinical manifestations of PD. We previously reported that DJ-1-/- mice display significant motor abnormalities and nigrostriatal DA functional deficits, though the number and morphology of DA neurons are normal up to the age of 12 months . Since aging is a major risk factor for PD, we analyzed older DJ-1-/- mice to determine whether aged DJ-1-/- mice developed PD-like pathology, such as degeneration of nigrostriatal DA neurons in the SN or noradrenergic neurons in the LC. Our quantitative analysis failed to detect any significant loss of DA neurons or noradrenergic neurons in aged DJ-1-/- mice at 24–27 months. We found that levels of striatal dopamine and its metabolites were normal. Additionally, there were no other neuropathological changes such as gliosis or protein aggregation in aged DJ-1-/- brains. Furthermore, we found no accumulation of oxidative damage in aged DJ-1-/- brains.
Despite the fact that multiple important functions associated with the pathogenesis of PD have been attributed to DJ-1, surprisingly, we found that loss of DJ-1 function in mice even at the age of 2 years did not cause significant loss of DA neurons. First, DJ-1 has been reported to function as an anti-oxidative stress agent through scavenging ROS [5–7]. However, we failed to find increases in immunoreactivities of oxidative damage markers in DJ-1-/- brains at the age of 24–27 months, suggesting the lack of accumulation of ROS in aged DJ-1-/- brains. It has been reported that expression of DJ-1 is induced in cells that have been subjected to oxidative stresses . Therefore, it is possible that DJ-1 plays a critical role in an environment with elevated oxidative stress; however, under normal conditions, DJ-1 is not required for nigral neuron survival. To examine whether DJ-1-/- mice have increased susceptibility to oxidative stress under oxidative conditions is an important question to be addressed in future studies. Second, it was reported that DJ-1 had chaperone activity and inhibited α-synuclein aggregation . Immunohistochemical studies in aged DJ-1-/- mice did not show any inclusions immunoreactive for α-synuclein or ubiquitin, indicating that loss of DJ-1 function is not enough to result in formation of these protein inclusions. It has been reported that these inclusions have been found in animal models treated with oxidative stimuli such as rotenone or MPTP [37, 38] and that the chaperone activity of DJ-1 can be stimulated by oxidation . Therefore, investigation of whether DJ-1 inactivation would accelerate protein aggregation under conditions of oxidative stimuli is necessary to understand the role of DJ-1 in chaperone activity and formation of Lewy bodies. Third, it has been suggested that DJ-1 might be involved in transcriptional regulation. DJ-1 transcriptionally up-regulates human TH by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor (PSF) . We however failed to detect reduced TH expression in DJ-1-/- mice even at the age of 2 years indicating that DJ-1 is not required in the transcriptional regulation of TH expression in mice.
In summary, despite the fact that loss of function mutations in DJ-1 cause PD and presumably nigral degeneration in humans, our current study failed to find DA neurodegeneration in DJ-1-/- mice during the life span of mice. In addition, although DJ-1 has been shown to protect cells from environmental oxidative stimuli, absence of DJ-1 did not cause accumulation of oxidative damage in aged DJ-1-/- mice under normal conditions. These results are consistent with our prior report showing that loss of parkin function alone in mice is also insufficient to cause loss of DA neurons up to the age of 2 years . Other possibilities, including shorter life span of mice, well-controlled mouse housing environment, may contribute to the absence of profound nigral degeneration that is characteristic of PD brains.
Open field: Male DJ-1-/- mice and wild-type littermates were tested in the open field using two acrylic animal cages. Each pair of both genotypic groups were placed into two cages at a time for 15 min during which their horizontal and vertical movements were monitored using 3 arrays of 16 infrared light beam sensors (AccuScan Instruments). The total number of movements, the distance traveled, the time spent moving and the total number of infrared beam breaks in both the horizontal plane and along the vertical axis were recorded and analyzed using AccuScan VersaMax software. Statistical differences between the two genotypes were assessed by Student's t-test. Rotarod: Male DJ-1-/- mice and wild-type littermates were also tested on the rotarod. Two pairs of both genotypic groups were placed at one time on the Economex accelerating rotarod (Columbus Instruments) equipped with individual timers for each mouse. Mice were initially trained to stay on the rod for 2 min at a constant rotation speed of 5 rpm. After a 2 min rest, mice were returned to the rotating rod at an accelerating speed of 0.2 rpm/sec, and the time of the mice remaining on the rotating rod was measured as latency to fall. A total of 3 trials were performed for each mouse. Acoustic Startle Reflex: Noise and prepulse generation were controlled by a computer. Each pair of both genotypic groups were placed in the two calibrated startle cylinders (Med Associates) and received a 5-min acclimation period without background noise before the startle stimuli. The testing session contained 50 trials and lasted 25 minutes, which consisted of twenty five pulses at 100 dB alone or twenty five 100 dB pulses preceded (100 ms) by prepulses of 80 dB in a semi-random order with a 30-second interval. The stimulation duration was 600 ms, while the duration of 100 dB pulses was 50 ms at frequencies of 5–40 kHz and the duration of the prepulses at 80 dB was 10 ms at a frequency of 10 kHz. Their responses were measured with a transducer that was attached to the underside of the platform and connected to the computer. Averages of peak values resulting from 100 dB pulses alone or 100 dB pulses coupled with 80 dB prepulses were calculated. %PPI was calculated using the following formula; 100 – (startle amplitude with PPI/startle amplitude alone) × 100. The data was evaluated with Student's t-test.
Histology and neuron counting
Mouse brains were dissected, formalin fixed for 2 h, processed for paraffin embedding, and sectioned in the coronal plane at 16 μm or 20 μm thickness. Each paraffin block contained 4 DJ-1-/- and 4 wild-type brains. Deparaffinized sections were immersed in a solution of 3% H2O2/methanol for 15 min. The sections were incubated in 10% normal goat serum (NGS)/phosphate buffered saline (PBS) for 1 h, and then were incubated with each appropriately diluted primary antibodies against DJ-1 (rabbit polyclonal; Signet), tyrosine hydroxylase (TH) (rabbit polyclonal; Chemicon), glial fibrillary acidic protein (GFAP) (mouse monoclonal; Sigma), α-synuclein (Syn-1; mouse monoclonal; BD Transduction Labs.), ubiquitin (rabbit polyclonal, DAKO), Michael adducts of 4HNE (rabbit polyclonal, Calbiochem), nitrotyrosine (rabbit polyclonal, Upstate) or DNA/RNA oxidative damage (mouse monoclonal, QED Bioscience) in 10% NGS/PBS at 4°C overnight. Rinsed sections were processed by Vectastain ABC kit (Vector Labs.) with the correct biotinylated secondary antibody, and the peroxidase reaction product was detected using DAB peroxidase substrate (Vector Labs.). The number of DA neurons in the SN was determined by counting TH immunoreactive neurons in coronal sections of four brains per genotype using the fractionator and optical dissector methods of unbiased stereology  under a Leica DMRB microscope equipped with a CCD camera connected to a computer running Bioquant image analysis software. The counting of the number of TH-positive cells in LC was performed by counting the cells in every 4 coronal sections (16 μm thickness) from the rostralmost to caudalmost limits of the LC [42, 43]. A TH-positive cell was defined as an immunoreactive somata with a clearly visible unstained nucleus, or a piece of a soma of comparable size. The cells were counted bilaterally in all sections per animal with a power (200X) using a light microscope. The total number of TH-positive LC neurons per animal was calculated by summing the bilateral TH-positive LC neurons in all sections from rostral to caudal. The experimenter was blind to the genotypes of mice. Values are reported as means ± SEM. Statistical differences were assessed by Student's t test.
Striatal dopamine and metabolites measurements by HPLC
Striata were dissected, weighed and stored at -80°C. Frozen striata were sonicated in ice-cold solution (0.1 N perchloric acid, 0.2 mM sodium bisulfite) and centrifuged for 20 min at 20,000 × g at 4°C. For dopamine measurement, the supernatant was filtered (0.2 μm) and applied to a C18 reverse phase HPLC column connected to an ESA model 5200A electrochemical detector with a 5014B microdialysis cell with potentials set to -175 mV and +200 mV using MD-TM mobile phase (ESA, Inc.) with isocratic elution. For metabolites measurement, the supernatant was applied to a 150 × 2.1 mm ID, C18 reverse phase HPLC column connected to an Alexys LC-100 system (Antec-Leyden) with electrochemical detection (DECADE II) and a VT-03 electrochemical flow cell using a detection potential of 590 mV and isocratic elution (50 mM phosphoric acid, 50 mM citric acid, 400 mg/ml OSA, 0.1 mM EDTA, 8 mM KCl, pH 3.75, 3% methanol) flowing at 0.2 ml/min.
The dorsal striata were dissected out and sonicated in 500 μL of 150 mM NaCl, 50 mM Tris, pH 7.4, 2 mM EDTA, 1% Nonidet P-40, 1% sodiumdeoxycholate, 1% sodium dodecylsulfate, protease inhibitors (Roche) and phosphatase inhibitors (Calbiochem). The protein content was analyzed by BCA assay (Pierce), and 10 μg of protein per lane was resolved on 4–12% gradient gels (Invitrogen), transferred to nitrocellulose membrane, blocked with 5% milk in TBST (50 mM Tris, pH 7.4, 150 mM NaCl, 0.1% Tween-20), and incubated with a primary antibody (TH, Chemicon) at 4°C overnight. The membrane was then incubated with a peroxidase-conjugated anti-rabbit antibody (Biorad), treated with chemiluminescence reagent (PerkinElmer Life Sciences) and exposed to film. Sample was reprobed with a primary antibody against α-tubulin (mouse monoclonal; Sigma) to confirm equal protein loading.
glial fibrillary acidic protein
high performance liquid chromatography
reactive oxygen species
We thank Tohru Kitada, Laura Corina and Lan Wang for assistance. This work was supported by grants from the NINDS (R01NS052745) and the Michael J. Fox Foundation.
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