Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's disease (PD) is caused by neuronal cell death, and oxidative stress and mitochondrial dysfunction are thought to be responsible for onset of PD. DJ-1, a causative gene product of a familial form of Parkinson's disease, PARK7, plays roles in transcriptional regulation and anti-oxidative stress. The possible mitochondrial function of DJ-1 has been proposed, but its exact function remains unclear. In this study, we found that DJ-1 directly bound to NDUFA4 and ND1, nuclear and mitochondrial DNA-encoding subunits of mitochondrial complex I, respectively, and was colocalized with complex I and that complex I activity was reduced in DJ-1-knockdown NIH3T3 and HEK293 cells. These findings suggest that DJ-1 is an integral mitochondrial protein and that DJ-1 plays a role in maintenance of mitochondrial complex I activity.
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PMID:DJ-1 binds to mitochondrial complex I and maintains its activity. 1982 28

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A progressive movement disorder typified by the production of bradykinesia, tremor, rigidity, and impairment of postural reflexes, PD is characterized by a depletion of dopamine in the striatum. For the last decade, several Mendelian forms of PD have been identified. Mutations in these genes potentially lead to autosomal dominant (alpha-synuclein and LRRK2), or autosomal recessive PD (Parkin, PINK1, DJ1, and ATP13A2). This article will spotlight these six distinct genes unambiguously associated with Mendelian PD and the function of their encoded proteins.
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PMID:From genes to proteins in mendelian Parkinson's disease: an overview. 1994 43

Loss of function of DJ-1 (PARK7) is associated with autosomal recessive early-onset Parkinson's disease (PD), one of the major age-related neurological diseases. In this study, we extended former studies on DJ-1 knockout mice by identifying subtle morphological and behavioural phenotypes. The DJ-1 gene trap-induced null mutants exhibit less dopamine-producing neurons in the ventral tegmental area (VTA). They also exhibit slight changes in behaviour, i.e. diminished rearing behaviour and impairments in object recognition. Furthermore, we detected subtle phenotypes, which suggest that these animals compensate for the loss of DJ-1. First, we found a significant upregulation of mitochondrial respiratory enzyme activities, a mechanism known to protect against oxidative stress. Second, a close to significant increase in c-Jun N-terminal kinase 1 phosphorylation in old DJ-1-deficient mice hints at a differential activation of neuronal cell survival pathways. Third, as no change in the density of tyrosine hydroxylase (TH)-positive terminals in the striatum was observed, the remaining dopamine-producing neurons likely compensate by increasing axonal sprouting. In summary, the present data suggest that DJ-1 is implicated in major non-motor symptoms of PD appearing in the early phases of the disease-such as subtle impairments in motivated behaviour and cognition-and that under basal conditions the loss of DJ-1 is compensated.
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PMID:DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments. 2003 49

Parkinson's disease (PD) is a common neurodegenerative disorder of unknown cause. For decades, a deficit in mitochondrial respiration was thought to be a key factor in PD neurodegeneration. However, excluding a few exceptions where a clinical picture of parkinsonism is associated with a mitochondrial DNA mutation, preclinical and clinical studies have failed to identify any genetic mutations in the genes encoding for the electron transport chain complexes in PD patients. More recently, it has been discovered that mutations in the genes encoding for Parkin, PINK1 and DJ1 are associated with familial forms of PD and with mitochondrial alterations, including morphological abnormalities. These results have led many researchers to revisit the question of mitochondrial biology as a primary mechanism in PD pathogenesis, this time from an angle of perturbation in mitochondrial dynamics and not from the angle of a deficit in respiration.
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PMID:Is there a pathogenic role for mitochondria in Parkinson's disease? 2008

Although a loss-of-function mutation has been identified in familial Parkinson's disease PARK7, the wild-type of DJ-1 is known to act as an oxidative stress sensor in neuronal cells. Recently, we identified UCP0045037 as a compound that bound to the reduced form of DJ-1 by in silico virtual screening. In this study, we determined the neuroprotective effects of UCP0045037 against focal cerebral ischemia-induced neurodegeneration in rats. Hydrogen peroxide-induced cell death was significantly inhibited by UCP0045037 in both rat mesencephalic dopaminergic neurons and human normal SH-SY5Y cells. In contrast, DJ-1-knockdown SH-SY5Y cells lost the protective activity of UCP0045037. These results suggest that UCP0045037 interacts with endogenous DJ-1 and produces a neuroprotective response.
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PMID:Oxidative neurodegeneration is prevented by UCP0045037, an allosteric modulator for the reduced form of DJ-1, a wild-type of familial Parkinson's disease-linked PARK7. 2008 65

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized alpha-synuclein (alpha-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of alpha-syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human alpha-syn (M83 mice) that develop extensive alpha-syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of alpha-syn inclusions, biochemical properties of alpha-syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate alpha-syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr alpha-syn in vivo. It is possible that alpha-syn and DJ-1 mutations may lead to PD via independent mechanisms.
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PMID:DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human alpha-syn toxicity. 2008 32

Loss-of-function DJ-1 (PARK7) mutations have been linked with a familial form of early onset Parkinson disease. Numerous studies have supported the role of DJ-1 in neuronal survival and function. Our initial studies using DJ-1-deficient neurons indicated that DJ-1 specifically protects the neurons against the damage induced by oxidative injury in multiple neuronal types and degenerative experimental paradigms, both in vitro and in vivo. However, the manner by which oxidative stress-induced death is ameliorated by DJ-1 is not completely clear. We now present data that show the involvement of DJ-1 in modulation of AKT, a major neuronal prosurvival pathway induced upon oxidative stress. We provide evidence that DJ-1 promotes AKT phosphorylation in response to oxidative stress induced by H(2)O(2) in vitro and in vivo following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Moreover, we show that DJ-1 is necessary for normal AKT-mediated protective effects, which can be bypassed by expression of a constitutively active form of AKT. Taken together, these data suggest that DJ-1 is crucial for full activation of AKT upon oxidative injury, which serves as one explanation for the protective effects of DJ-1.
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PMID:DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway. 2013 95

Over the past decade, major progress has been achieved in the identification of genes associated with Parkinson's disease (PD) and parkinsonism. Five genes have now been shown conclusively to play a role in PD susceptibility. Mutations in three of these genes, PRKN, PINK1, and DJ1, are important in early onset, recessively inherited PD, while mutations in LRRK2 and SNCA result in autosomal-dominant PD. LRRK2 has emerged as the most prevalent genetic cause of PD and has been implicated in both familial and sporadic forms of disease. In addition, autosomal-dominant dementia and Parkinsonism has been shown to be caused by mutations in the MAPT and PGRN genes. Molecular tests are now commercially available for several of these genes; however, in some of them, positive results need to be interpreted with caution until penetrance is better understood. In addition, clinical treatment of PD remains largely unaltered by the results of genetic testing.
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PMID:Clinical implications of gene discovery in Parkinson's disease and parkinsonism. 2018 45

Mutations in Cu/Zn superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), which could be attributed to the toxic properties of the misfolded protein, oxidative stress, and mitochondrial dysfunction. DJ-1 - a causative agent of familial Parkinson's disease PARK7 - is responsible for inducing antioxidative reaction. In this study, we showed the up-regulation of DJ-1 protein levels in mutant SOD1 transgenic mice through the lifespan were observed in the motor neurons. We demonstrated biochemically DJ-1 formed complexes with mutant SOD1 in the cell lysates. Furthermore, DJ-1 over-expression resulted in increased cell viability and reduced cell toxicity in mutant SOD1-transfected neuronal cells, because of improvement in apoptotic pathway and reduction in oxidative stress levels. We also evaluated DJ-1 levels in CSF collected from sporadic ALS patients and controls subjects. The CSF DJ-1 levels were significantly higher in patients with sporadic ALS than in control subjects. These results show that DJ-1 may be associated with sporadic and familial ALS pathogenesis. Therefore, insight into the effects of DJ-1 on mutant SOD1-mediated toxicity may provide a therapeutic advance for the treatment of motor neuron degeneration in ALS.
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PMID:DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity. 2020 83

The molecular mechanisms leading to neurodegeneration in Parkinson's disease remain elusive. Deletion and mutations of DJ-1 (PARK7) have been reported to cause autosomal recessive familial Parkinson's disease. Wildtype DJ-1 scavenges H(2)O(2) by cysteine oxidation in response to oxidative stress, and thus confers neuroprotection. Activation of the transcription factor NF-E2-related factor-2 (Nrf2) has also been shown to be important for protection against oxidative stress in many models of neurodegenerative diseases. Previous data indicate that DJ-1 affects the transcriptional functions and stability of Nrf2. However, this observation has not been confirmed. In the current study, the role of DJ-1 in the regulation of Nrf2 is examined in primary cultured neurons, astrocytes and in vivo. The prototypical Nrf2 activator tBHQ protected primary cortical neurons derived from DJ-1-knockout (KO) as well as DJ-1 wildtype mice by activation of Nrf2-ARE pathway. Nrf2 nuclear translocation, robust increases in canonical Nrf2-driven genes and proteins, and dramatic activation of the ARE reporter gene, hPAP, were observed after tBHQ treatment. These results were further confirmed by siRNA-mediated DJ-1 knockdown in primary cortical astrocytes from ARE-hPAP mice and tBHQ administration into the striatum of mouse brain. In addition, overexpression of Nrf2 with adenovirus preferentially in astrocytes from DJ-1-KO mice enhanced survival of neurons under oxidative insults. These findings indicate that activation of the Nrf2-ARE pathway is independent of DJ-1, and Nrf2 activation is a potential therapeutic target to prevent neurodegeneration in sporadic and DJ-1 familial Parkinson's disease.
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PMID:Keap1-Nrf2 activation in the presence and absence of DJ-1. 2037 12


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