Sci. Aging Knowl. Environ., 11 January 2006
Vol. 2006, Issue 2, p. pe2
[DOI: 10.1126/sageke.2006.2.pe2]

PERSPECTIVES

Lessons from Drosophila Models of DJ-1 Deficiency

Darren J. Moore, Valina L. Dawson, and Ted M. Dawson

The authors are at the Institute for Cell Engineering (D.J.M., V.L.D., T.M.D.) and the Departments of Neurology (D.J.M., V.L.D., T.M.D.), Neuroscience (V.L.D., T.M.D.), and Physiology (V.L.D.) at the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. E-mail: dmoore20{at}jhmi.edu (D.J.M.), vdawson{at}jhmi.edu (V.L.D.), tdawson{at}jhmi.edu (T.M.D.)

http://sageke.sciencemag.org/cgi/content/full/2006/2/pe2

Key Words: Parkinson's disease (PD) • PARK7 • DJ-1 • Drosophila melanogaster • oxidative stress • paraquat • dopaminergic • neurodegeneration

Introduction: DJ-1 and Parkinson's Disease

Parkinson's disease (PD) is a common neurodegenerative movement disorder primarily characterized by the progressive loss of neurons containing the neurotransmitter dopamine from a region of the brain called the substantia nigra pars compacta (see Andersen Review). Most cases of PD are sporadic in origin, but a small proportion are familial. The recent identification of genes that, when mutated, give rise to rare familial forms of parkinsonism has provided important insight into the pathogenesis of PD. Mutations in five genes unambiguously cause familial forms of the disease: {alpha}-synuclein, parkin, DJ-1, PINK1, and LRRK2 (1-3). Of these, {alpha}-synuclein and LRRK2 mutations manifest disease in an autosomal dominant manner, whereas mutations in the remaining genes cause a recessive form of the disease. Although much research in recent years has tended to focus on the role played by {alpha}-synuclein and parkin in PD, mutations in DJ-1, PINK1, and LRRK2 have only been identified in the past 3 years, and thus their contribution to the pathogenesis of PD is still being realized. Of these three genes, our knowledge of DJ-1 is currently the most advanced, owing mainly to its earlier discovery.

Mutations in the DJ-1 gene are associated with the PARK7 locus and, so far, have proved to be an extremely rare cause of inherited and sporadic parkinsonism, being much less common than mutations in parkin, LRRK2, and PINK1 (4-6). A number of exonic deletions, truncations, missense mutations, and intronic splice site mutations in the DJ-1 gene have been identified in PD cohorts. Most PD patients have either homozygous or compound heterozygous DJ-1 mutations, but some also have single heterozygous mutations, suggesting that DJ-1 loss-of-function accounts for disease in these individuals. These findings have presented the opportunity to develop model organisms that recapitulate DJ-1-linked parkinsonism by generating homozygous null alleles for DJ-1. To this end, DJ-1-deficient mouse models and, more recently, Drosophila melanogaster models have been developed to further investigate the contribution of DJ-1 dysfunction to the pathogenesis of PD (7-13). DJ-1-deficient mice largely fail to provide a convincing model of parkinsonism in that they fail to exhibit degeneration of substantia nigra or other neurons but do display some consistent features, including deficits in locomotor function and impaired neurotransmission in nigrostriatal dopaminergic (DA) neurons (7-9). Instead, studies in DJ-1-deficient mice and primary neuronal cultures derived from these mice have consistently revealed a striking sensitivity to oxidative stimuli, including hydrogen peroxide, rotenone, and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) (9, 14), all of which share the capacity to impair normal mitochondrial function. These exciting findings suggest an important role for DJ-1 in conferring neuroprotection specifically toward oxidative stress in vivo (see Giasson Perspective), consistent with the current contention that DJ-1 most likely functions as a redox-sensitive molecular chaperone with particular relevance to mitochondrial stress (2, 15-19) (Fig. 1).



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Fig. 1. Overview of the putative function of DJ-1 and its relation to mitochondria. Human DJ-1 exists as an obligate homodimer normally present both in the cytoplasm and within the mitochondrial matrix and intermembrane space. Oxidative modification of DJ-1, mainly by reactive cysteine residues (particularly Cys106), may result in translocation of DJ-1 to the outer membrane of mitochondria. DJ-1 may thus function, in part, as a redox sensor that responds to increased ROS concentrations. DJ-1 is normally imported into mitochondria through an unknown mechanism. Human DJ-1 has been shown to possess chaperone-like activity in vitro, and shares closest structural homology with the Escherichia coli and Saccharomyces cerevisiae molecular chaperone, Hsp31, as determined by x-ray crystallography studies. In cell culture models and in vivo, DJ-1 confers robust protection against the deleterious effects of a wide range of oxidative stimuli, many of which selectively impair mitochondrial function (MPP+, rotenone, and paraquat). (MPP+ is the active metabolite of MPTP, required for use in cell culture; MPTP is used in animal models in which glial cells later process this substance into active MPP+.) This protection is likely mediated by the chaperone-like activity of DJ-1 but also, in part, by direct antioxidant scavenging activity. Oxidative stress, mediated mainly by ROS, can increase protein misfolding and inhibit proteasomal function. Accordingly, DJ-1 can protect against proteasomal inhibition, endoplasmic reticulum (ER) stress, and the toxicity associated with overexpression of mutant {alpha}-synuclein and the parkin substrate Pael-R, all of which share the capacity to increase protein misfolding and subsequent proteolytic stress. Protection against protein misfolding is likely afforded by the chaperone-like activity of DJ-1. This model is based on references (2, 4, 9-20, 28-30, 33-35). H2O2, hydrogen peroxide; MPP+, 1-methyl-4-phenylpyridinium; 6-OHDA, 6-hydroxy-dopamine; {alpha}-Syn, {alpha}-synuclein; Pael-R, parkin-associated endothelin receptor-like receptor; Cys, cysteine.

 
Drosophila Models of DJ-1 Deficiency: Different Methodologies, Distinct Phenotypes

In the past few months, four independent studies have described the effects of DJ-1 loss-of-function in Drosophila and its potential relevance to the pathogenesis of PD (10-13). Although these studies clearly provide an important advance in our knowledge of DJ-1 function, the results have been largely disparate because of the different methodological approaches employed by each study (summarized in Fig. 2). In particular, DJ-1 expression has been disrupted through a combination of genomic microdeletion (11, 12) or insertion (10) mediated by transposable P elements, or through transgenic RNA interference (RNAi) (13). In contrast to mammalian species, which contain a single DJ-1 gene, Drosophila possess two closely-related orthologs of DJ-1, termed DJ-1{alpha} and DJ-1beta, both with significant yet equivalent similarity (~70%) to the human protein sequence. DJ-1beta exhibits a ubiquitous expression pattern throughout Drosophila, including the brain, and is expressed at all developmental stages from embryo to adult. In contrast, DJ-1{alpha} expression is largely restricted to the testes and is detected only in the later stages of development concomitant with the appearance of male reproductive organs. However, DJ-1{alpha} expression has also been detected, albeit at low concentrations, in the brain by reverse transcription-polymerase chain reaction, which suggests that both fly homologs may play a role in the brain (11).



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Fig. 2. Summary of key features of DJ-1-deficient Drosophila models. DM, dorsomedial; Ref, reference.

 
Three of the Drosophila studies have employed P element-based methods to create microdeletions or insertional mutations in one or both DJ-1 genes. Primarily, the consensus has been to disrupt the DJ-1beta gene because of its abundant expression in the adult fly brain and because of its ubiquitous expression profile similar to that of human DJ-1. P element-based gene disruption is a convenient and efficient method to create mutant or null alleles. Genomic microdeletions were generated by induced transposition of a defined P element inserted in or around either DJ-1 gene, with subsequent selection against a P element-associated marker to create microdeletions that can be precisely mapped across the gene (11, 12). This technique is probably the most favorable method to disrupt the DJ-1 gene, because microdeletions encompassing most, if not all, of the coding regions and untranslated regulatory elements can be created. Genomic P element insertions were created by a similar method termed "local hopping" to select for transposition events into the nearby DJ-1 gene to create an insertional mutation (10). This latter method has a potential confounding issue in that genomic regulatory elements can be retained and transcripts still synthesized, which in some cases might lead to the creation of hypomorphic rather than null alleles. Such differences between the methods used to create DJ-1 null alleles can produce distinct phenotypes. However, DJ-1-deficient Drosophila models created by P element-based gene disruption methods fail to recapitulate a parkinsonian phenotype in that they lack the progressive degeneration of DA neurons.

Models generated by genomic microdeletion

Meulener and colleagues (11) created a DJ-1-deficient model by generating flies null for both DJ-1 homologs [that is, double knockouts (DKOs)] by P element-mediated microdeletion to overcome the potential redundant function of both DJ-1 homologs. DJ-1 DKO flies are viable, fertile, and display a normal life span. Aged DJ-1 DKO flies exhibit a full complement of DA neurons in all well-characterized DA clusters, including the dorsomedial cluster, as measured by confocal microscopy of whole-mount immunostained serial sections. Drosophila contain approximately 200 neurons that can secrete the neurotransmitter dopamine (that is, DA neurons), and these are arranged into a number of discrete clusters (DA clusters) throughout the brain in a bilateral symmetric fashion. DJ-1 DKO flies display a striking sensitivity to oxidative stimuli, including paraquat, hydrogen peroxide, and rotenone, which can be rescued by ubiquitous transgenic overexpression of either or both DJ-1 homologs. This result indeed suggests that Drosophila DJ-1 homologs are functionally redundant but most likely serve distinct roles in different tissues or cells. Although exposure to oxidative stimuli reduces the survival rate of DJ-1 DKO flies, intriguingly the numbers of DA neurons are not altered under these conditions, perhaps suggesting that they are not selectively vulnerable in this model. This finding further suggests that frank loss of DA neurons does not compromise the survival of these flies upon exposure to oxidative stimuli. The authors performed similar studies in single DJ-1 knockout (KO) flies, which suggested that the increased sensitivity to paraquat exposure is mediated entirely by the absence of DJ-1beta but not DJ-1{alpha}, which may reflect the differential expression patterns of both homologs. Furthermore, similar to human DJ-1, endogenous DJ-1beta appears to be modified to a more acidic form in response to paraquat exposure, consistent with oxidative modification of conserved cysteine residues (15, 20). This fly DJ-1 DKO model highlights the important role played by both DJ-1 homologs in conferring protection against oxidative stress but suggests that DJ-1beta likely serves a more prominent role in Drosophila because of its ubiquitous expression pattern. DA neurons lacking both DJ-1 homologs do not exhibit increased sensitivity to oxidative stress, arguing against a specific neuroprotective role for either DJ-1 homolog in this model. However, as with all KO models that fail to show an expected phenotype, one can not rule out a potential compensatory mechanism that results specifically from germline disruption of one or both DJ-1 genes to promote DA neuron survival.

Park and colleagues (12) elected to disrupt the DJ-1beta gene by P element-mediated microdeletion to create a different fly model, which largely exhibits a phenotype similar to the DKO fly model reported by Meulener and coworkers (11). Although aged DJ-1beta KO flies display a full complement of DA neurons in all defined clusters, they still appear to display an impaired climbing ability, as measured by negative geotaxis [a test of locomotor skill defined by the ability of flies to vertically ascend (climb)], which is progressive with age. However, transgenic rescue experiments were not performed to determine whether this locomotor deficit is specifically mediated by DJ-1beta loss-of-function or whether perhaps it relates to differences in the genetic background of the wild-type control fly strain versus the DJ-1beta KO fly strain--a possibility because this phenotype was observed even in 1-day-old flies. A locomotor deficit in the absence of observable DA neuronal loss is reminiscent of the phenotype displayed by some DJ-1 KO mouse models (7, 8) and might indicate an early impairment in DA neurotransmission. Exposure of KO but not wild-type flies to paraquat leads to a further decrease in climbing ability, suggesting that DJ-1beta KOs are selectively vulnerable to oxidative stimuli. Findings with this fly model tend to reinforce the notion that DJ-1beta plays an important role in conferring protection against oxidative stress but may not play a prominent role in promoting the survival of DA neurons.

Models generated by genomic insertional inactivation

Menzies and colleagues (10) relied on P element-mediated insertional inactivation (via "local hopping") of the DJ-1beta gene to create a third Drosophila model. In stark contrast to the phenotype of DJ-1beta null flies generated by genomic microdeletions (11, 12), loss of DJ-1beta expression in this fly model actually leads to the increased survival of DA neurons with age, which becomes apparent only in 60-day-old flies. The increased survival of DA neurons was specific to particular DA neuron clusters, including the dorsomedial cluster (protocerebral posterior medial 1/2) and the protocerebral posterior lateral 1 and 2 clusters, but did not influence the survival of serotoninergic neurons, which primarily contain the neurotransmitter serotonin. (It is difficult to say whether such neurons are specifically affected in PD, as many neuronal subgroups become affected in the latter stages of this disease.) The two previously mentioned studies of DJ-1-deficient fly models did not analyze flies beyond 30 days old and thus may have overlooked such a phenotype. Coupled with increased survival of DA neurons, these DJ-1beta mutant flies also displayed marked protection against paraquat exposure but were strikingly sensitive to hydrogen peroxide exposure. Resistance to paraquat appears to be mediated by DJ-1{alpha}, which is up-regulated approximately two-fold in the brains of these DJ-1beta mutant flies. Consistent with this observation, transgenic overexpression of DJ-1{alpha} in DA neurons of wild-type flies selectively conferred protection against exposure to paraquat but not to hydrogen peroxide. Thus, it appears that germline disruption of the DJ-1beta gene by P element-mediated insertion leads to a compensatory up-regulation of DJ-1{alpha} expression in the adult fly brain, perhaps hinting at a coordinately regulated mechanism of gene expression of both DJ-1 homologs. It is unclear at present whether DJ-1beta expression can reciprocally be up-regulated in DJ-1{alpha} mutant flies. Furthermore, although both DJ-1 homologs show some functional redundancy in one fly model discussed earlier (11), this model clearly highlights a functional preference for protection of DA neurons against paraquat exposure but not hydrogen peroxide exposure by DJ-1{alpha}. Alternatively, such selective protection might also be related to the differential mechanisms of toxicity of paraquat versus hydrogen peroxide in DA neurons, because the nigrostriatal neuronal pathway in mice is thought to be selectively vulnerable to systemic paraquat exposure (21). Although DJ-1beta mutant flies are sensitive to hydrogen peroxide exposure, it remains to be determined whether DJ-1beta mutants similarly display sensitivity to paraquat exposure in the absence of a compensatory up-regulation of DJ-1{alpha}. Insight from other DJ-1beta null flies would suggest that this homolog can protect against most forms of oxidative stress, including paraquat. The selective preservation of DA neurons with age in DJ-1beta mutant flies also highlights an important protective role for DJ-1{alpha} in the fly brain in promoting the survival of DA neurons, whereas analysis of other fly models would suggest that DJ-1beta does not have this capacity (11, 12). The compensatory effect of DJ-1{alpha} in this DJ-1beta mutant fly might further suggest that as yet uncharacterized compensatory mechanisms may similarly be at work in other DJ-1beta null flies, perhaps leading to the preservation of DA neuron number.

Models generated by transgenic RNAi

A fourth DJ-1 mutant fly model, generated by transgenic RNAi, complicates the picture still further. Yang and coworkers (13) chose to knock down DJ-1{alpha} expression, which could be effectively achieved at both the mRNA and protein levels by transgenic RNAi with no obvious effects on DJ-1beta expression. A major caveat of this RNAi model is the inability to account for "off-target" effects of RNAi, because only a single DJ-1{alpha} double-stranded RNA (dsRNA) molecule was employed in flies with no appropriate dsRNA controls (such as a mismatched or scrambled dsRNA sequence) in some instances. Despite this oversight, knockdown of DJ-1{alpha} expression leads to a strikingly robust neurodegenerative phenotype in Drosophila, which, if independently reproducible, promises to be an important model for DJ-1-associated parkinsonism. Ubiquitous transgenic expression of DJ-1{alpha} dsRNA resulted in larval lethality, suggesting an essential function for DJ-1{alpha} in flies despite its restricted expression pattern. Tissue-specific knockdown of DJ-1{alpha} was accomplished by using the widely employed GAL4/UAS bipartite system, in which the expression of the nucleotide sequence of interest, placed downstream of a GAL4-responsive upstream activating sequence (UAS) element, is achieved by driving expression of the GAL4 transcription factor using a tissue- or cell-specific promoter element. The use of eye-specific GAL4 drivers leads to eye degeneration (manifested as a rough eye phenotype) with some photoreceptor neuron loss that can be partially rescued by overexpression of DJ-1{alpha} or human DJ-1. This latter finding suggests for the first time a certain degree of functional conservation between fly and human DJ-1 orthologs.

Intriguingly, expression of DJ-1{alpha} dsRNA in DA neurons using neuronal-specific GAL4 drivers also leads to an age-dependent loss of DA neurons in the dorsomedial cluster and to a related decrease in brain dopamine content. The authors analyzed neurons positive for tyrosine hydroxylase (the rate-limiting enzyme for dopamine biosynthesis and a useful highly specific marker for DA neurons) in paraffin-embedded sections by light microscopy to determine DA neuron number, a technique that has come under increasing scrutiny recently because of an inherent level of variability and that has been largely superseded by whole-mount immunostaining with confocal microscopy as the "gold standard" (22-24). The use of this technique has led to the controversy surrounding the phenotypic reproducibility of the original {alpha}-synuclein transgenic Drosophila model (23, 25, 26). The authors also failed to analyze different DA neuron clusters or other non-DA neurons in the fly brain to ascertain whether the loss of dorsomedial DA neurons was a specific effect of DJ-1{alpha} knockdown. The finding that brain dopamine content was reduced before observable neuronal loss indicates that DJ-1{alpha} might play a role in regulating dopamine concentration despite its relative scarcity in the brain. The initial results from this RNAi fly model suggest that DJ-1{alpha} is an essential gene that is critical for the survival of DA neurons and eye photoreceptors and that its absence leads to a progressive neurodegenerative phenotype. Perhaps the major difference between this RNAi-based model and the P element-based DJ-1 DKO model (11) discussed above is the expected lack of compensatory mechanisms thought to occur by disrupting gene expression at a posttranscriptional level versus genomic microdeletion. Compensatory mechanisms in response to a germline genomic microdeletion might be acquired, or positively selected for, to ensure successful embryonic development or might result from disrupting genes that are coordinately regulated together with other gene sets. In contrast, because RNAi targets mRNA, this technique should not therefore interfere with gene regulation. Additionally, it can also be used in a tissue or cell-specific manner, thus potentially avoiding compensatory mechanisms during embryogenesis. Perhaps a similar compensatory phenomenon might be at work in mouse models of DJ-1 deficiency, thus accounting for their inability to mimic the human disease (7-9). One also must not overlook the potential "off-target" effects often associated with the use of RNAi (27), and future experiments using additional DJ-1{alpha} dsRNAs will help to address the specificity and reproducibility of this RNAi-based fly model. Seemingly at odds with the restricted expression pattern of DJ-1{alpha} are its potent survival promoting qualities in the fly brain and eye. It will be of great interest to determine the effects of DJ-1beta knockdown in the fly brain by transgenic RNAi, because one might expect a similar, if not more potent, neurodegenerative phenotype on the basis of its ubiquitous expression pattern in Drosophila and its protective properties against oxidative insult (11, 12).

Similar to other DJ-1 mutant fly models, the DJ-1{alpha} RNAi fly model also appears to display marked sensitivity to oxidative stress. RNAi knockdown of DJ-1{alpha} using a pan-neuronal GAL4 driver leads to a reduced survival rate of flies after exposure to hydrogen peroxide and 3-amino-triazole (3-AT), a compound that inhibits catalase, an antioxidant enzyme that converts hydrogen peroxide to water. Consistent with a neuroprotective role for DJ-1{alpha} against oxidative stress, ubiquitous overexpression of DJ-1{alpha} increases the resistance of wild-type flies to 3-AT treatment. This finding contrasts somewhat with those reported by Menzies and co-workers, who demonstrated that overexpression of DJ-1{alpha} in DA neurons conferred no protection against hydrogen peroxide treatment (10), indicating that the protective effects of DJ-1{alpha} specifically against hydrogen peroxide are probably mediated in a brain- or tissue-wide manner and are not simply limited to DA neurons. Neuronal cultures from the DJ-1{alpha} RNAi Drosophila model display an increase in reactive oxygen species (ROS) as compared with wild-type neurons observed by dichlorofluorescin diacetate staining, an indicator of hydroxyl free radicals. Furthermore, DJ-1{alpha} also displays weak hydrogen peroxide scavenging activity in vitro when compared with catalase. These findings illuminate the normal role of DJ-1{alpha} in critically regulating ROS concentrations in a manner that probably does not depend on direct antioxidant scavenging activity but is more consistent with a role as a sensor of redox status, similar to the biological function proposed for human DJ-1 (15, 16, 28-30). A preexisting elevation of ROS concentrations would also explain the heightened sensitivity of the DJ-1{alpha} RNAi flies to additional oxidative stress.

Finally, Yang and colleagues have made important use of the robust neurodegenerative phenotype in their RNAi fly model to perform genetic interaction studies with candidate genes and pathways (13). Using the DJ-1{alpha} RNAi-induced eye degeneration phenotype as an indicator, they detected a specific genetic interaction between DJ-1{alpha} and the prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway (see figure 1 in Longo Perspective) but not with the mitogen-activated protein kinase or JNK pathways. Eye degeneration was enhanced by overexpression of the pro-apoptotic protein, PTEN, an antagonist of PI3K, or by a dominant-negative form of PI3K, and was suppressed by overexpression of PI3K or Akt. Similarly, overexpression of PI3K suppressed the reduction in DA neurons induced by DJ-1{alpha} RNAi, whereas a dominant-negative form of PI3K enhanced DA neuronal loss. Neuronal loss induced by DJ-1{alpha} RNAi may be related to increased ROS concentrations in the fly brain, and the protective effects afforded by PI3K/Akt pathway up-regulation might act specifically through suppressing these elevated ROS concentrations. Further linking the DJ-1{alpha} RNAi-induced neurodegenerative phenotype to the PI3K/Akt pathway is the observation that the concentration of phosphorylated, and hence activated, Akt is reduced in the brains of these flies, suggesting an impairment in PI3K/Akt signaling. A similar reduction in Akt phosphorylation was also noted in parkin RNAi flies, perhaps implying a critical role for PI3K/Akt signaling in the pathogenesis of PD. The genetic interaction of DJ-1{alpha} with the PI3K/Akt pathway in Drosophila is highly consistent with the emerging role of human DJ-1 as a novel negative regulator of PTEN function (31).

Lessons from Drosophila Models: A Neuroprotective Role for DJ-1 Against Oxidative Stress

It is presently difficult to reconcile all aspects of the various Drosophila models of DJ-1 deficiency. Models with targeted germline disruption of DJ-1 genes do not produce a parkinsonian phenotype or neurodegenerative disease, perhaps suggesting strong compensatory up-regulation of neuroprotective genes; in one particular model, up-regulation of DJ-1{alpha} is observed (10). Such Drosophila models are reminiscent of DJ-1-deficient mice, which also lack frank neuronal degeneration. These observations may be telling us something about the chronic nature of neurodegeneration in PD, with perhaps the life span of flies and mice exceeding the onset of disease in the context of compensatory effects. Thus, at best, DJ-1-deficient flies and mice may represent pre-symptomatic models of PD, with possibly a second pathogenic "hit" being required to precipitate neuronal degeneration in the presence of compensatory mechanisms. In both cases, this second "hit" might be oxidative stress, as both DJ-1-deficient flies and mice are acutely and, for the most part, selectively vulnerable to a wide range of oxidative stimuli. This sensitivity of flies and mice to oxidative stress in the absence of DJ-1 strongly suggests that DJ-1 orthologs share potent protective qualities against oxidative stress in vivo. A major link between DJ-1 and oxidative stress is compatible with our current understanding of the molecular pathogenesis of PD, in which post-mortem studies in PD brains have consistently revealed marked indices of oxidative and nitrosative stress in affected regions (32).

The striking neurodegenerative phenotype observed in Drosophila with conditional knockdown of DJ-1{alpha} expression by RNAi suggests that (i) the application of RNAi-based approaches may overcome confounding compensatory mechanisms to precipitate neuronal degeneration during the life span of flies and (ii) that DJ-1{alpha} has a prominent protective role in the brain by promoting the survival of DA neurons, largely consistent with the fly model developed by Menzies and colleagues (10). It will be of great importance to address the possibility of similar compensatory mechanisms in the mouse through RNAi-based approaches to knock down DJ-1 expression in the brain or specific neuronal populations. The big issues now for the use of RNAi-based approaches to create models of DJ-1 deficiency are reproducibility and specificity, as well as the need to carefully control for potential "off-target" effects often associated with RNAi (27). Collectively, all Drosophila models of DJ-1 deficiency suggest important yet distinct roles for both DJ-1{alpha} and DJ-1beta homologs in conferring substantial neuroprotection toward oxidative stress. The next important step will be to decipher the precise mechanism by which DJ-1, a putative redox-sensitive molecular chaperone (Fig. 1), normally regulates the balance of ROS and counteracts the deleterious effects of oxidative stress.


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Citation: D. J. Moore, V. L. Dawson, T. M. Dawson, Lessons from Drosophila Models of DJ-1 Deficiency. Sci. Aging Knowl. Environ. 2006 (2), pe2 (2006).








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